4-aminobutanoic acid derivatives and drugs containing these derivatives as the active ingredient

ABSTRACT

Aminobutylic acid derivatives of the formula (I)                    
     wherein the symbols are as defined in specification; and non-toxic salts thereof. Because of inhibiting matrix metalloproteinase, the compounds of the formula (I) are useful for prevention and/or treatment of diseases, for example, rheumatoid diseases, arthrosteitis, osteoarthritis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, cornea ulcer, metastasis, invasion or growth of tumor cells, autoimmune disease, disease caused by vascular emigration or infiltration of leukocytes, arterialization, multiple sclerosis, arota aneurysm, endometriosis, restenosis after PTCA, unstable angina, acute myocardial infarction, transient ischemic attack.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 application of International Application No.PCT/JP00/02191, filed Apr. 5, 2000, claiming the benefit of JapanesePatent Application No.11-98453, filed Apr. 6, 1999, the entiredisclosures of which are incorporated herein by reference.

TECHNICAL FIELD

This invention relates to aminobutyric acid derivatives, processes forthe preparation thereof and pharmaceutical agents comprisingaminobutyric acid derivatives as active ingredient.

More particularly, this invention relates to:

[1] aminobutyric acid derivatives of the formula (I):

wherein all the symbols are as hereinafter defined, and non-toxic saltsthereof, processes for the preparation thereof and pharmaceutical agentscomprising aminobutyric acid derivatives as active ingredient, and

[2] a compound which is selected from

(1)5-ethoxymethoxy-4(S)-[N-(4-iodophenylcarbonyl)amino]pentanoic acid,

(2)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-methoxymethylpentanoicacid,

(3)2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,

(4) 5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(5)5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(6)2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(7)5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(8)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxyhenylcarbonyl)amino]pentanoicacid,

(9)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-(2-furyl)phenylcarbonyl)amino]pentanoicacid,

(10)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-ethoxymethylpentanoicacid,

(11)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(12)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanoicacid,

(13)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanoicacid,

(14)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanoicacid,

(15)5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanoicacid,

(16)5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,

(17)5-methoxyethoxymethoxy-2(S)-methyl-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(18)trans-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexanoic acid,

(19)trans-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexanoicacid,

(20)trans-2-[(4-nitrophenylcarbonyl)amino]cyclohexylacetic acid,

(21)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,

(22)N-hydroxy-2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(23)N-hydroxy-5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(24)N-hydroxy-5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(25)N-hydroxy-2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(26)N-hydroxy-5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(27)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxyphenylcarbonyl)amino]pentanamide,

(28)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-(2-furyl)phenylcarbonyl)amino]pentanamide,

(29)N-hydroxy-5-ethoxymethoxy-2(R)-ethoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,

(30)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(31)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,

(32)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanamide,

(33)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,

(34)N-hydroxy-5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanamide,

(35)N-hydroxy-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(36)N-hydroxy-2(S)-methyl-5-methoxyethoxymethoxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,

(37)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(38)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,

(39)N-hydroxy-2(S)-(2-benzothiophen-3-yl)methyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,

(40)N-hydroxy-2(S)-allyl-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,

(41)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-bromophenylcarbonyl)amino]pentanamide,

(42)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,

(43)N-hydroxy-2(S)-methyl-5-hydroxy-4(S)-[N-methyl-N-[(5-nitro-2-thienyl)carbonyl]amino]pentanamide,

(44)N-hydroxy-2(S)-benzyl-5-hydroxy-4(S)-[N-methyl-N-[(5-bromo-2-thienyl)carbonyl]amino]pentanamide,

(45)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexane,

(46)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexane,

(47)trans-1-(N-hydroxyaminocarbonylmethyl)-2-[(4-nitrophenylcarbonyl)amino]cyclohexane,

and methyl ester, t-butyl ester, benzyl ester, allyl ester, andnon-toxic salts thereof, and pharmaceutical agents comprising thecompound and non-toxic salts thereof as active ingredient.

BACKGROUND ART

The matrix metalloproteinases (MMPs) are neutral metalloproteinases andzinc (Zn²⁺) is essential in the active site for their activation. Theydegrade collagen, laminin, proteoglycans, fibronectin, elastin, gelatinetc. under physiological conditions and therefore, are effective ongrowth and tissue remodeling of articulation tissue, bone tissue andconnective tissue. At least 10 classes of MMPs, which differ in primarystructure, are identified. Concretely, there are InterstitialCollagenase (MMP-1), Neutrophil Collagenase (MMP-8), Gelatinase A(MMP-2), Gelatinase B (MMP-9), Stromelysin-1 (MMP-3), Stromelysin-2(MMP-10), Matrilysin (MMP-7), metalloelastase (MMP-12) etc.

As common characteristics of these enzymes, MMPs

(1) have Zn²⁺ in the active site and the activity depends on calcium ion(Ca²⁺)

(2) are secreted as an inactive proenzyme and activated outside ofcells,

(3) have high homology on amino acid sequence,

(4) have an ability to degrade on various extracellular matrixcomponents in vivo,

(5) are regulated by tissue inhibitors of metalloproteinases (TIMP)which are specific to MMPs.

MMP inhibitors are useful for prevention and/or treatment of variousdiseases induced by overexpression and excess activation of MMP. Suchdiseases are, for example, rheumatoid diseases, arthrosteitis,osteoarthritis, unusual bone resorption, osteoporosis, periodontitis,interstitial nephritis, arteriosclerosis, pulmonary emphysema,cirrhosis, cornea injury, cornea ulcer, metastasis, invasion or growthof tumor cells, autoimmune disease (Crohn's disease, Sjogren'ssyndrome), disease caused by vascular emigration or infiltration ofleukocytes, arterialization, multiple sclerosis, aorta aneurysm,endometriosis, restenosis after PTCA, unstable angina, acute myocardialinfarction, transient ischemic attack.

Some compounds possessing inhibitory activity against MMP are known. Asequence in the vicinity of cleavage site of collagen (Gly-Ile-Ala-Glyor Gly-Leu-Ala-Gly) has high affinity for collagenase. Much research anddevelopment on substrate analogous MMP inhibitors, which are chemicallymodified so as to have zinc affinity groups on a cleaving site of thesubstrate, has energetically been carried out [Inhibitors of matrixmetalloproteinases (MMP's), Nigel R A Beeley, Phillip R J Ansell, AndrewJ P Docherty et. al., Curr. Opin. Ther. Patents., A, 7-16 (1994),Current Drugs Ltd ISSN 0962-2594]. However, these substrate-analoguesinhibitors might have various problems. Therefor, it is desired toobtain a non-peptide inhibitor and some compounds are reported.

For example, in the specification of EP 757037 as the Example,sulfonylamino acid derivatives of the formula (W):

are disclosed to have an activity of inhibiting matrixmetalloproteinase.

In the specification of EP 757984 as the Example, hydroxamic acidderivatives of the formula (X):

are disclosed to have an activity of inhibiting matrixmetalloproteinase.

DISCLOSURE OF THE INVENTION

Energetic investigations have been carried out in order to make aninhibitor for matrix metalloproteinase, e.g. gelatinase, stromelysin orcollagenase. The present inventors have found that aminobutyric acidderivatives of the formula (I), which are carboxylic amino derivativesof γ-amino acid accomplished the present purpose.

The present invention relates to:

[1] aminobutyric acid derivatives of the formula (I):

 wherein

R¹ is —COOR¹⁰, —CONHOR¹⁰, —CONHNHR¹⁰, —(CH₂)_(n)SR⁵⁰ or —Y—PO(OR⁵¹)₂;

R¹⁰ is (i) hydrogen, (ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv) phenyl,(v) C1-8 alkyl substituted by phenyl or C1-8 alkoxy, or (vi) oxycarbonylsubstituted by phenyl, benzyl or C1-8 alkyl;

n is 0-3;

R⁵⁰ is (i) hydrogen, (ii) C1-8 alkyl, (iii) —COR⁵², in which R⁵² is C1-8alkyl or phenyl, (iv) —SR⁵³, in which R⁵³ is hydrogen, C1-8 alkyl orphenyl;

R⁵¹ is hydrogen, C1-8 alkyl or phenyl;

Y is a single bond, —CH₂— or —O—;

R², R³, R⁴, R⁵, R⁶ and R⁷ each, independently, is

(1) hydrogen,

(2) C1-8 alkyl,

(3) C2-8 alkenyl,

(4) —OR¹¹,

(5) —SR¹¹,

(6) —NR¹²R¹³,

(7) Cyc1,

(8) C1-8 alkyl substituted by one or more groups selected from —OR¹¹,—SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1,

(9) C2-8 alkenyl substituted by one or more groups selected from —OR¹¹,—SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1,

(10) C2-8 alkynyl,

(11) C1-8 alkyl substituted by one or more groups selected from C3-8alkenyloxy, with the proviso that a group having a double bond at1-position is excluded; and C3-8 alkynyloxy, with the proviso that agroup having a triple bond at 1-position is excluded; or

R³ and R⁴, taken together is C1-8 alkylene, R⁵and R⁶, taken together isC1-8 alkylene, R³ and R⁶, taken together is C1-8 alkylene, R² and R³,taken together is C2-8 alkylene, R⁴ and R⁵, taken together is C2-8alkylene, or R⁶ and R⁷, taken together is C2-8 alkylene;

in which Cyc1 is carbocyclic ring or heterocyclic ring and thesecarbocyclic ring and heterocyclic ring may be substituted by one or moreof (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v)amidino, (vi) halogen atoms, (vii) cyano (viii) hydroxy, (ix) benzyloxy,(x) —NR¹⁰¹R¹⁰², in which R¹⁰¹ and R¹⁰² each, independently, is hydrogenor C1-8 alkyl, (xi) —COOR¹⁰³, in which R¹⁰³ is hydrogen or C1-8 alkyl,(xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv)phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii)phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or cyano, (xix)heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxy substituted by—CONR¹⁰⁴R¹⁰⁵, in which R¹⁰⁴ and R¹⁰⁵ each, independently, is hydrogen,C1-8 alkyl or phenyl;

R¹¹ is

(i) hydrogen,

(ii) C1-8 alkyl,

(iii) Cyc1,

(iv) —COR¹⁸,

(v) C1-8 alkyl substituted by one or more groups selected from —OR¹⁵,—SR¹⁵, —NR¹⁶R¹⁷, —COR¹⁸, guanidino and Cyc1;

R¹⁵ is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1 orC1-8 alkoxy;

R¹⁶ is hydrogen or C1-8 alkyl;

R¹⁷ is hydrogen, C1-8 alkyl or —COR¹⁹, in which R¹⁹ is C1-8 alkyl, Cyc1,C1-8 alkyl substituted by Cyc1;

R¹⁸ is hydroxy, C1-8 alkyl, C1-8 alkoxy or —N ²⁰R²¹, in which R²⁰ andR²¹, each independently, is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkylsubstituted by Cyc1;

R¹² is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1;

R¹³ is hydrogen, C1-8 alkyl, Cyc1, C1-8 alkyl substitutedby Cyc1, or—COR²², in which R²² is C1-8 alkyl, Cyc1 or C1-8 alkyl substituted byCyc1;

R¹⁴ is hydroxy, C1-8 alkyl, C1-8 alkoxy, Cyc1, C1-8 alkyl substituted byCyc1, or —NR²³R²⁴, in which R²³ and R²⁴, each ndependently, is (i)hydrogen, (ii) C1-8 alkyl, (iii) Cyc1 or (iv) C1-8 alkyl substituted byCyc1 or hydroxy;

(1) when R⁸ is

1) hydrogen,

2) C1-8 alkyl,

3) C1-8 alkoxycarbonyl,

4) C1-8 alkyl substituted by one or more groups selected from —OR²⁶,—SR²⁶, —NR²⁷R²⁸ and —COR²⁹, or

5) C1-8 alkoxycarbonyl substituted by Cyc2,

R⁹ is

(2) when R⁸ is

R⁹ is

1) C1-8 alkyl,

2) C1-8 alkoxy,

3) C1-8 alkoxy substituted by Cyc2,

4) C1-8 alkyl substituted by one or more groups selected from —OR²⁶,—SR²⁶, —NR²⁷R²⁸, —COR²⁹ and Cyc2, or

5)

 in which Cyc2 is carbocyclic ring or heterocyclic ring and thesecarbocyclic ring and heterocyclic ring may be substituted by one or moreof (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v)amidino, (vi) halogen atoms, (vii) cyano, (viii) hydroxy, (ix)benzyloxy, (x) —NR²⁰¹R²⁰², in which R²⁰¹ and R²⁰² each, independently,is hydrogen or C1-8 alkyl, (xi) —COOR²⁰³, in which R²⁰³ is hydrogen orC1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv)phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi)phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted byphenyl or cyano, (xix) heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxysubstituted by —CONR²⁰⁴R²⁰⁵ in which R²⁰⁴ and R²⁰⁵ each, independently,is hydrogen, C1-8 alkyl or phenyl;

R²⁶ is hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2;

R²⁷ is hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2;

R²⁸ is hydrogen, C1-8 alkyl, Cyc2, C1-8 alkyl substituted by Cyc2, or—COR³⁰, in which R³⁰ is C1-8 alkyl, Cyc2 or C1-8 alkyl substituted byCyc2;

R²⁹ is hydroxy, C1-8 alkyl, Cyc2, C1-8 alkyl substituted by Cyc2, or—NR³¹R³², in which R³¹ and R³², each independently, is hydrogen, C1-8alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2;

 is carbocyclic ring or heterocyclic ring;

R²⁵ is —E—G;

E is

1) a single bond,

2) —CONR³³—,

3) —NR³³CO—,

4) —CO—O—,

5) —O—CO—,

6) —NR³³—CO—NR³⁴—,

7) —CO—CH₂—,

8) —CO—,

9) —O—CO—NR³³—,

10) —NR³³—CO—O—,

11) —O—CO—O—,

12) —CS—NR³³—,

13) —NR³³—CS—,

14) —CS—O—,

15) —O—CS—,

16) —NR³³—CS—NR³⁴—,

17) —CS—CH₂—,

18) —CS—,

19) —O—CS—NR³³—,

20) —NR³³—CS—O—,

21) —O—CS—O—,

22) —CH₂—CH₂—,

23) —HC═CH—,

24) —C≡C—,

25) —SO₂—NR³³—,

26) —NR³³—SO₂—,

27) —SO₂—CH₂— or

28) —CH₂—SO₂—;

R³³ and R³⁴, each independently, is hydrogen, C1-8 alkyl, Cyc3 or C1-8alkyl substituted by Cyc3;

Cyc3 is carbocyclic ring or heterocyclic ring and these carbocyclic ringand heterocyclic ring may be substituted by one or more of (i) C1-8alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi)halogen atoms, (vii) cyano, (viii) hydroxy, (ix) benzyloxy, (x)—NR³⁰¹R³⁰², in which R³⁰¹ and R³⁰² each, independently, is hydrogen orC1-8 alkyl, (xi) —COOR³⁰³, in which R³⁰³ is hydrogen or C1-8 alkyl,(xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv)phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii)phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or cyano, (xix)heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxy substituted by—CONR³⁰⁴R³⁰⁵, in which R³⁰⁴ and R³⁰⁵ each, independently, is hydrogen,C1-8 alkyl or phenyl;

G is

1) hydrogen,

2) C1-8 alkyl,

3) Cyc4,

4) —OR³⁵,

5) —SR³⁵,

6) halogen atoms,

7) nitro,

8) cyano,

9) —NR³⁶R³⁷,

10) —COR³⁸,

11) C1-8 alkyl substituted by one or more groups selected from Cyc4,—OR³⁵, —SR³⁵ ₁ halogen atoms, —NR³⁶R³⁷ and —COR³⁸;

in which Cyc4 is carbocyclic ring or heterocyclic ring and thesecarbocyclic ring and heterocyclic ring may be substituted by one or moreof (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v)amidino, (vi) halogen atoms, (vii) cyano, (viii) hydroxy, (ix)benzyloxy, (x) —NR⁴⁰¹R⁴⁰², in which R⁴⁰¹ and R⁴⁰² each, independently,is hydrogen or C1-8 alkyl, (xi) —COOR⁴⁰³, in which R⁴⁰³ is hydrogen orC1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv)phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi)phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted byphenyl or cyano, (xix) heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxysubstituted by —CONR⁴⁰⁴R⁴⁰⁵ in which R⁴⁰⁴ and R⁴⁰⁵ each, independently,is hydrogen, C1-8 alkyl or phenyl;

R³⁵ is hydrogen, C1-8 alkyl, C1-8 alkoxy, Cyc4 or C1-8 alkyl substitutedby Cyc4;

R³⁶ is hydrogen, C1-8 alkyl, Cyc4, C1-8 alkyl substituted by Cyc4;

R³⁷ is hydrogen, C1-8 alkyl, Cyc4, C1-8 alkyl substituted by Cyc4, or—COR³⁹, in which R³⁹ is C1-8 alkyl, Cyc4 or C1-8 alkyl substituted byCyc4;

R³⁸ is hydroxy, C1-8 alkyl, Cyc4, C1-8 alkyl substituted by Cyc4, or—NR⁴⁰R⁴¹, in which R⁴⁰ and R⁴¹, each independently, is hydrogen, C1-8alkyl, Cyc4 or C1-8 alkyl substituted by Cyc4; or

—E—G taken together, is C1-4 alkylidene;

p is 1-5;

M is C1-8 alkylene;

J is a single bond, an oxygen atom, a sulfur atom or —NR⁴²—, in whichR⁴² is hydrogen or C1-8 alkyl;

is a single bond, or a double bond which prepared by two hydrogens arereleased, in the case of two of R², R³, R⁴, R⁵, R⁶ and R⁷ which do notbond to a same carbon atom but bond to a neighboring carbon, arehydrogens; with the proviso that

is not a double bond, when R³ and R⁴, taken together is C1-8 alkylene,R⁵ and R⁶, taken together is C1-8 alkylene, R³ and R⁶, taken together isC1-8 alkylene;

with the proviso that (1) at least one of R², R³, R⁴, R⁵, R⁶ and R⁷isC2-8 alkynyl, or C1-8 alkyl substituted by one or more groups selectedfrom C3-8 alkenyloxy and C3-8 alkynyloxy,

(2) when

 is benzene, and E is a single bond, then G is not hydrogen;

 non-toxic acid thereof, a process for the preparation thereof, and apharmaceutical agent comprising the same,

[2] a compound which is selected from

(1)5-ethoxymethoxy-4(S)-[N-(4-iodophenylcarbonyl)amino]pentanoic acid,

(2)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-methoxymethylpentanoicacid,

(3)2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(4)5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(5)5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(6)2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(7)5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(8)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxy-henylcarbonyl)amino]pentanoicacid,

(9)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-(2-furyl)phenylcarbonyl)amino]pentanoicacid,

(10)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-ethoxymethylpentanoicacid,

(11)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(12)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanoicacid,

(13)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanoicacid,

(14)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanoicacid,

(15)5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanoicacid,

(16)5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,

(17)5-methoxyethoxymethoxy-2(S)-methyl-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanoicacid,

(18)trans-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexanoic acid,

(19)trans-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexanoicacid,

(20) trans-2-[((nitrophenylcarbonyl)amino]cyclohexylacetic acid,

(21)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,

(22)N-hydroxy-2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(23)N-hydroxy-5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(24)N-hydroxy-5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(25)N-hydroxy-2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(26)N-hydroxy-5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(27)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxyphenylcarbonyl)amino]pentanamide,

(28)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-(2-furyl)phenylcarbonyl)amino]pentanamide,

(29)N-hydroxy-5-ethoxymethoxy-2(R)-ethoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,

(30)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(31)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,

(32)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanamide,

(33)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,

(34)N-hydroxy-5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanamide,

(35)N-hydroxy-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(36)N-hydroxy-2(S)-methyl-5-methoxyethoxymethoxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,

(37)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,

(38)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,

(39)N-hydroxy-2(S)-(2-benzothiophen-3-yl)methyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,

(40)N-hydroxy-2(S)-allyl-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,

(41)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-bromophenylcarbonyl)amino]pentanamide,

(42)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,

(43)N-hydroxy-2(S)-methyl-5-hydroxy-4(S)-[N-methyl-N-[(5-nitro-2-thienyl)carbonyl]amino]pentanamide,

(44)N-hydroxy-2(S)-benzyl-5-hydroxy-4(S)-[N-methyl-N-[(5-bromo-2-thienyl)carbonyl]amino]pentanamide,

(45)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexane,

(46)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexane,

(47)trans-1-(N-hydroxyaminocarbonylmethyl)-2-[(4-nitrophenylcarbonyl)amino]cyclohexane,

 and methyl ester, t-butyl ester, benzyl ester, allyl ester, andnon-toxic salts thereof, and pharmaceutical agents comprising thecompound and non-toxic salts thereof as active ingredient.

More particularly, this invention relates to:

[1] (A) the compound of the formula (I) wherein at least one of R², R³,R⁴, R⁵, R⁶ and R⁷ is C1-8 alkyl substituted by one or more groupsselected from C3-8 alkenyloxy and C3-8 alkynyloxy, non-toxic saltsthereof, a process for the preparation thereof, and a pharmaceuticalagent comprising the same, (B) the compound of the formula (I) whereinR², R³, R⁴, R⁵, R⁶ and R⁷each, independently, is (1) hydrogen, (2) C1-8alkyl, (3) C2-8 alkenyl, (4) —OR¹¹, (5) —SR¹¹, (6) —NR¹²R¹³, (7) Cyc1,(8) C1-8 alkyl substituted by one or more groups selected from —OR¹¹,—SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, (9) C2-8 alkenylsubstituted by one or more groups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³,—COR¹⁴, guanidino and Cyc1, (10) C2-8 alkynyl, or R³ and R⁴, takentogether is C1-8 alkylene, R⁵andR⁶, taken together is C1-8 alkylene, R³and R⁶ ₁ taken together is C1-8 alkylene, R² and R³, taken together isC2-8 alkylene, R⁴ and R⁵s taken together is C2-8 alkylene, or R⁶and R⁷,taken together is C2-8 alkylene, and at least one of R², R³, R⁴, R⁵, R⁶and R⁷ is C2-8 alkynyl,

 non-toxic salts thereof, a process for the preparation thereof, and apharmaceutical agent comprising the same,

[2] the above compound (1)-compound (47), non-toxic salts thereof and apharmaceutical agent comprising the same.

More particularly about (B) in the above [1],

(B-a) the compound of the formula (I) wherein R² is 2-propynyl, and R³,R⁴, R⁵, R⁶ and R⁷ each, independently, is (1) hydrogen, (2) C1-8 alkyl,(3) C2-8 alkenyl, (4) —OR¹¹, (5) —SR¹¹, (6) —NR¹²R¹³, (7) Cyc1, (8) C1-8alkyl substituted by one or more groups selected from —OR¹¹, —SR¹¹,—NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, or (9) C2-8 alkenyl substituted byone or more groups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴,guanidino and Cyc1, or R³ and R⁴, takentogether is C1-8 alkylene, R⁵andR⁶, taken together is C1-8 alkylene, R³ and R⁶, taken together is C1-8alkylene, R⁴ and R⁵, taken together is C2-8 alkylene, or R⁶ and R⁷,taken together is C2-8 alkylene, non-toxic salts thereof, a process forthe preparation thereof, and a pharmaceutical agent comprising the same,and

(B-b) the compound of the formula (I) wherein R², R³, R⁴, R⁵, R⁶ and R⁷each, independently, is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl,(4) —OR¹¹, (5) —SR11, (6) —NR¹²R¹³, (7) Cyc1, (8) C1-8 alkyl substitutedby one or more groups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴,guanidino and Cyc1, (9) C2-8 alkenyl substituted by one or more groupsselected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, or(10) C2-8 alkynyl, or R³ and R⁴, taken together is C1-8 alkylene, R⁵andR⁶, taken together is C1-8 alkylene, R³ and R⁶, taken together is C1-8alkylene, R² and R³, taken together is C2-8 alkylene, R⁴ and R⁵, takentogether is C2-8 alkylene, or R⁶ and R⁷, taken together is C2-8alkylene, and at least one of R², R³, R⁴, R⁵, R⁶ and R⁷ is C2-8 alkynyl,with the exclusion of the following compound:

the compound wherein R² is 2-propynyl, and R³, R⁴, R⁵, R⁶ and R⁷ each,independently, is the above groups (1)˜(9), or R³ and R⁴, taken togetheris C1-8 alkylene, R⁵ and R⁶, taken together is C1-8 alkylene, R³ and R⁶,taken together is C1-8 alkylene, R⁴ and R⁵, taken together is C2-8alkylene, or R⁶and R⁷, taken together is C2-8 alkylene;

 non-toxic salts thereof, a process for the preparation thereof, and apharmaceutical agent comprising the same.

More particularly about the above (B-b),

(B-b1) the compound of the formula (I) wherein R² is (1) hydrogen, (2)C1-8 alkyl, (3) C2-8 alkenyl, (4) —OR¹¹, (5) —SR¹¹, (6) —NR¹²R¹³, (7)Cyc1, (8) C1-8 alkyl substituted by one or more groups selected from—OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, or (9) C2-8 alkenylsubstituted by one or more groups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³,—COR¹⁴, guanidino and Cyc1, and R³, R⁴, R⁵, R⁶and R⁷each, independently,is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) —OR¹¹, (5) —SR¹¹,(6) —NR¹²R¹³, (7) Cyc1, (8) C1-8 alkyl substituted by one or more groupsselected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, (9)C2-8 alkenyl substituted by one or more groups selected from —OR¹¹,—SR¹¹, —NR¹²R¹³, —COR¹⁴ ₁ guanidino and Cyc1, or (10) C2-8 alkynyl, orR³and R⁴, taken together is C1-8 alkylene, R⁵ and R⁶, taken together isC1-8 alkylene, R³ and R⁶, taken together is C1-8 alkylene, R² and R³,taken together is C2-8 alkylene, R⁴and R⁵, taken together is C2-8alkylene, or R⁶ and R⁷, taken together is C2-8 alkylene, and at leastone of R³, R⁴, R⁵, R⁶ and R⁷ is C2-8 alkynyl,

 non-toxic salts thereof, a process for the preparation thereof, and apharmaceutical agent comprising the same,

(B-b2) the compound of the formula (I) wherein R² is C2-8 alkynyl, andR³, R⁴, R⁵, R⁶ and R⁷ each, independently, is (1) hydrogen, (2) C1-8alkyl, (3) C2-8 alkenyl, (4) —OR¹¹, (5) —SR¹¹, (6) —NR¹²R¹³, (7) Cyc1,(8) C1-8 alkyl substituted by one or more groups selected from —OR¹¹,—SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, (9) C2-8 alkenylsubstituted by one or more groups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³,—COR¹⁴, guanidino and Cyc1, or (10) C2-8 alkynyl, or R³ and R⁴, takentogether is C1-8 alkylene, R⁵and R⁶ ₁, taken together is C1-8 alkylene,R³ and R⁶, taken together is C1-8 alkylene, R⁴ and R⁵, taken together isC2-8 alkylene, or R⁶ and R⁷, taken together is C2-8 alkylene, and atleast one of R³, R⁴, R⁵, R⁶ and R⁷ is C2-8 alkynyl, non-toxic saltsthereof, a process for the preparation thereof, and a pharmaceuticalagent comprising the same, and

(B-b3) the compound of the formula (I) wherein R² is C2 alkynyl,1-propynyl, C4-8 alkynyl, and R³, R⁴, R⁵, R⁶ and R⁷ each, independently,is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) —OR¹¹, (5) —SR¹¹,(6) —NR¹²R¹³, (7) Cyc1, (8) C1-8 alkyl substituted by one or more groupsselected from —OR¹¹, —SR¹¹, —NR¹²R¹³ ₁, —COR¹⁴, guanidino and Cyc1, or(9) C2-8 alkenyl substituted by one or more groups selected from —OR¹¹,—SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, or R³ and R⁴, takentogether is C1-8 alkylene, R⁵and R⁶, taken together is C1-8 alkylene, R³and R⁶, taken together is C1-8 alkylene, R⁴ and R⁵, taken together isC2-8 alkylene, or R⁶ and R⁷, taken together is C2-8 alkylene,

 non-toxic salts thereof, a process for the preparation thereof, and apharmaceutical agent comprising the same.

In the present invention, C1-8 alkyl is methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl and isomeric groups thereof.

C1-8 alkoxy is methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy,heptyloxy, octyloxy and isomeric groups thereof.

C1-8 alkyl substituted byphenyl is methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl and isomeric groups thereof substituted by one ofphenyl.

C1-8 alkyl substituted by C1-8 alkoxy is methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl and isomeric groups thereof substituted byone of methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy,octyloxy and isomeric groups thereof.

C1-8 alkyl substituted by cyano is methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl and isomeric groups thereof substituted by one ofcyano.

C1-8 alkyl substituted by C3-8 alkenyloxy is methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereofsubstituted by 2-propenyloxy, 2-butenyloxy, 3-butenyloxy, pentenyloxy,hexenyloxy, heptenyloxy, octenyloxy, pentadienyloxy, hexadienyloxy,heptadienyloxy, octadienyloxy, hexatrienyloxy, heptatrienyloxy,octatrienyloxy and isomeric groups thereof.

C1-8 alkyl substituted by C3-8 alkynyloxy is methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereofsubstituted by 2-propynyloxy, 2-butynyloxy, 3-butynyloxy, pentynyloxy,hexynyloxy, heptynyloxy, octynyloxy and isomeric groups thereof.

C1-8 alkyl substituted by hydroxy is methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl and isomeric groups thereof substituted byone of hydroxy.

Oxycarbonyl substituted by phenyl is phenyloxycarbonyl.

Oxycarbonyl substituted by benzyl is benzyloxycarbonyl.

Oxycarbonyl substituted by C1-8 alkyl is methyloxycarbonyl,ethyloxycarbonyl, propyloxycarbonyl, butyloxycarbonyl,pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyland isomeric groups thereof.

C2-8 alkenyl is vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl,octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl,hexatrienyl, heptatrienyl, octatrienyl and isomeric groups thereof.

C2-8 alkynyl is ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl,hexynyl, heptynyl, octynyl and isomeric groups thereof.

C1-8 alkylene is methylene, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, heptamethylene, octamethylene, andisomeric groups thereof.

C2-8 alkylene is ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene, and isomeric groupsthereof.

Halogen atom is chlorine, bromine, fluorine, or iodine.

C1-8 alkoxycarbonyl is methyloxycarbonyl, ethyloxycarbonyl,propyloxycarbonyl, butyloxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl and isomericgroups thereof.

C1-4 alkylidene is methylidene, ethylidene, propylidene, butylidene andisomeric groups thereof.

Carbocyclic ring is C3-15 mono-, bi- or tri-carbocyclic ring, forexample, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclopentene, cyclohexene, cyclopentadiene,cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene,fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene,perhydropentalene, perhydroindene, perhydronaphthalene, perhydroazulene,perhydrofluorene, perhydrophenanthrene, perhydroanthracene,perhydroacenaphthylene, perhydrobiphenylene, adamantane, norcarane.

Heterocyclic ring is 5-18 membered mono-, bi- or tri-heterocyclic ringcontaining 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s).5-18 membered mono-, bi- or tri-heterocyclic ring containing 1-4 ofnitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) includes 5-18membered mono-, bi- or tri-heterocyclic aryl containing 1-4 ofnitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s), partially orfully saturated thereof.

5-18 membered mono-, bi- or tri-heterocyclic aryl containing 1-4 ofnitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s), is, for example,pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin,oxazepine, thiophene, thiain (thiopyran), thiepin, oxazole, isoxazole,thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzothiazole, benzoimidazole, carbazole or acridine.

Partially or fully saturated 5-18 membered mono-, bi- ortri-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s)and/or 1-2 of sulfur(s) is, for example, pyrroline, pyrrolidine,imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline,tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine,tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine,dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyran),tetrahydrothiain (tetrahydrothiopyran), dihydrooxazole,tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole,dihydrothiazole, tetrahydrothiazole, dihydroisothiazole,tetrahydroisothiazole, morpholine, thiomorpholine, indoline,isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine,benzoazepine, benzodiazepine, indolooxazepine,indolotetrahydrooxazepine, indolooxadiazepine,indolotetrahydrooxadiazepine, indolothiazepine,indolotetrahydrothiazepine, indolothiadiazepine,indolotetrahydrothiadiazepine, indoloazepine, indolotetrahydroazepine,indolodiazepine, indolotetrahydrodiazepine, benzofurazan,benzothiadiazole, benzotriazole, camphor, imidazothiazole,dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole,dihydroacridine, tetrahydroacridine, perhydroacridine, dioxolane,dioxane, dithiolane, dithiane, dioxazine, dithiazine,7-oxabicyclo[4.1.0]heptane.

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkenylene, alkynylene, alkoxy, andalkylene include straight-chain and branched-chain ones. Moreover, theisomers in the structure of a double bond, ring, fused ring (E, Z. cis,trans), the isomers generated by the presence of asymmetric carbonatom(s) etc. (R, S isomers, α, β isomers, enantiomers, diastereomers)optically active isomers having optical rotation (D, L, d, 1 isomers),isomers separated by chromatography (more polar or less polar isomers),equilibrium compounds, compounds of arbitrary ratio of these compounds,racemic mixtures are included in the present invention.

[Salts]

Non-toxic salts of the compound (I) of the present invention include allpharmaceutically acceptable salts, for example, general salts, acidaddition salts, hydrate salts.

The compounds of formula (I) and the present compounds of (1)˜(47) maybe converted into the corresponding salts. Non-toxic and water-solublesalts are preferred. Suitable salts, for example, include:

salts of alkali metals (e.g. potassium, sodium), salts of alkaline earthmetals (e.g. calcium, magnesium), ammonium salts, salts ofpharmaceutically acceptable organic amines (e.g. tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)amine, lysine, arginine,N-methyl-D-glucamine).

The compounds of the present invention of formula (I) and the presentcompound (1)-compound (47) may be converted into the corresponding acidaddition salts. Non-toxic salts and water-soluble salts are preferred.Suitable salts, for example, include:

salts of inorganic acids e.g. hydrochloride, hydrobromide, hydroiodide,sulfate, phosphate, nitrate; salts of organic acids e.g. acetate,trifluoroacetate, lactate, tartarate, oxalate, fumarate, maleate,citrate, benzoate, methanesulphonate, ethanesulphonate,benzenesulphonate, toluenesulphonate, isethionate, glucuronate,gluconate.

The compounds of the present invention of formula (I), the presentcompound (1)-compound (47) and salts thereof may be converted into thecorresponding hydrates by conventional means.

In the compound of the formula (I), a preferred combination of R², R³,R⁴, R⁵, R⁶ and R⁷ is that:

[1] R² is C1-8 alkyl substituted by one or more groups selected fromC3-8 alkenyloxy and C3-8 alkynyloxy, R³, R⁴, R⁵ and R⁷ are hydrogen, andR⁶ is 1) hydrogen, 2) C1-8 alkyl, 3)C2-8 alkenyl, 4) —OR¹¹, 5) —SR¹¹, 6)—NR¹²R¹³, 7) Cyc1, 8) C1-8 alkyl substituted by one or more groupsselected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, 9)C2-8 alkenyl substituted by one or more groups selected from —OR¹¹,—SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, 10) C2-8 alkynyl, 11) C1-8alkyl substituted by one or more groups selected from C3-8 alkenyloxyand C3-8 alkynyloxy; specially preferred R⁶ is 8) C1-8 alkyl substitutedby one or more groups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴,guanidino and Cyc1, 9) C2-8 alkenyl substituted by one or more groupsselected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1;

[2] R² is 2-propynyl, R³, R⁴, R⁵ and R⁷ are hydrogen, and R⁶ is 1)hydrogen, 2) C1-8 alkyl, 3) C2-8 alkenyl, 4) —OR¹¹, 5) —SR¹¹, 6)—NR¹²R¹³, 7) Cyc1, 8) C1-8 alkyl substituted by one or more groupsselected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, 9)C2-8 alkenyl substituted by one or more groups selected from —OR¹¹,—SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1; specially preferred R⁶ is8) C1-8 alkyl substituted by one or more groups selected from —OR¹¹,—SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, 9) C2-8 alkenyl substitutedby one or more groups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴,guanidino and Cyc1;

[3] R⁶ is C2-8 alkynyl, R³, R⁴, R⁵ and R⁷ are hydrogen, and R² is 1)hydrogen, 2) C1-8 alkyl, 3) C2-8 alkenyl, 4) —OR¹¹, 5) —SR¹¹, 6)—NR¹²R¹³, 7) Cyc1, 8) C1-8 alkyl substituted by one or more groupsselected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, 9)C2-8 alkenyl substituted by one or more groups selected from —OR¹¹,—SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1; specially preferred R² is2) C1-8 alkyl, 8) C1-8 alkyl substituted by one or more groups selectedfrom —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, 9) C2-8 alkenylsubstituted by one or more groups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³,—COR¹⁴, guanidino and Cyc1;

[4] R² is C2-8 alkynyl, R³, R⁴, R⁵ and R⁷ are hydrogen, and R⁶ is C2-8alkynyl;

[5] R²is C2 alkynyl (ethynyl), 1-propynyl, C4-8 alkynyl (butynyl,pentynyl, hexynyl, heptynyl, octynyl or isomeric groups thereof), R³,R⁴, R⁵ and R⁷are hydrogen, and R⁶ is 1) hydrogen, 2) C1-8 alkyl, 3) C2-8alkenyl, 4) —OR¹¹, 5) —SR¹¹, 6) —NR¹²R¹³, 7) Cyc1, 8) C1-8 alkylsubstituted by one or more groups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³,—COR¹⁴, guanidino and Cyc1, 9) C2-8 alkenyl substituted by one or moregroups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1;specially preferred R⁶ is 8) C1-8 alkyl substituted by one or moregroups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR₁₄, guanidino and Cyc1,9) C2-8 alkenyl substituted by one or more groups selected from —OR¹¹,—SR¹¹, —NR¹²R¹³, —COR¹⁴.

In the compound of formula (I), preferred are the compound of theformula (Ia)

wherein G¹ is methyl, halogen atoms, nitro, cyano or phenoxy, and theother symbols are as hereinbefore defined; or the compound of theformula (Ib):

wherein G² is methyl, halogen atoms, nitro or cyano, the other symbolsare as hereinbefore defined.

Concretely, the compounds in the Table 1-Table 25, non-toxic saltsthereof and the compounds described in Example are preferable. Besides,in the following table, EOM means ethoxymethyl, a mark “*” in theformula means an asymmetric carbon, and each of R, S and RS isomers isincluded.

TABLE 1 (I-A1)

No. R¹ R⁸ R⁹ 1 COOH H

2 COOH H

3 COOH H

4 COOH H

5 COOH H

6 COOH H

7 COOH —CH₃

8 COOH —CH₃

9 COOH —CH₃

10  COOH —CH₃

11  COOH —CH₃

12  COOH —CH₃

TABLE 2 (I-A2)

No. R¹ R⁸ R⁹ 1 CONHOH H

2 CONHOH H

3 CONHOH H

4 CONHOH H

5 CONHOH H

6 CONHOH H

7 CONHOH —CH₃

8 CONHOH —CH₃

9 CONHOH —CH₃

10  CONHOH —CH₃

11  CONHOH —CH₃

12  CONHOH —CH₃

TABLE 3 (I-A3)

No. R¹ R⁸ R⁹ 1 CONHNH₂ H

2 CONHNH₂ H

3 CONHNH₂ H

4 CONHNH₂ H

5 CONHNH₂ H

6 CONHNH₂ H

7 CONHNH₂ —CH₃

8 CONHNH₂ —CH₃

9 CONHNH₂ —CH₃

10  CONHNH₂ —CH₃

11  CONHNH₂ —CH₃

12  CONHNH₂ —CH₃

TABLE 4 (I-A4)

No. R¹ R⁸ R⁹ 1 CH₂—SH H

2 CH₂—SH H

3 CH₂—SH H

4 CH₂—SH H

5 CH₂—SH H

6 CH₂—SH H

7 CH₂—SH —CH₃

8 CH₂—SH —CH₃

9 CH₂—SH —CH₃

10  CH₂—SH —CH₃

11  CH₂—SH —CH₃

12  CH₂—SH —CH₃

TABLE 5 (I-A5)

No. R¹ R⁸ R⁹ 1 PO(OH)₂ H

2 PO(OH)₂ H

3 PO(OH)₂ H

4 PO(OH)₂ H

5 PO(OH)₂ H

6 PO(OH)₂ H

7 PO(OH)₂ —CH₃

8 PO(OH)₂ —CH₃

9 PO(OH)₂ —CH₃

10  PO(OH)₂ —CH₃

11  PO(OH)₂ —CH₃

12  PO(OH)₂ —CH₃

TABLE 6 (I-B1)

No. R¹ R⁸ R⁹ 1 COOH H

2 COOH H

3 COOH H

4 COOH H

5 COOH H

6 COOH H

7 COOH —CH₃

8 COOH —CH₃

9 COOH —CH₃

10  COOH —CH₃

11  COOH —CH₃

12  COOH —CH₃

TABLE 7 (I-B2)

No. R¹ R⁸ R⁹ 1 CONHOH H

2 CONHOH H

3 CONHOH H

4 CONHOH H

5 CONHOH H

6 CONHOH H

7 CONHOH —CH₃

8 CONHOH —CH₃

9 CONHOH —CH₃

10  CONHOH —CH₃

11  CONHOH —CH₃

12  CONHOH —CH₃

TABLE 8 (I-B3)

No. R¹ R⁸ R⁹ 1 CONHNH₂ H

2 CONHNH₂ H

3 CONHNH₂ H

4 CONHNH₂ H

5 CONHNH₂ H

6 CONHNH₂ H

7 CONHNH₂ —CH₃

8 CONHNH₂ —CH₃

9 CONHNH₂ —CH₃

10  CONHNH₂ —CH₃

11  CONHNH₂ —CH₃

12  CONHNH₂ —CH₃

TABLE 9 (I-B4)

No. R¹ R⁸ R⁹ 1 CH₂—SH H

2 CH₂—SH H

3 CH₂—SH H

4 CH₂—SH H

5 CH₂—SH H

6 CH₂—SH H

7 CH₂—SH —CH₃

8 CH₂—SH —CH₃

9 CH₂—SH —CH₃

10  CH₂—SH —CH₃

11  CH₂—SH —CH₃

12  CH₂—SH —CH₃

TABLE 10 (I-B5)

No. R¹ R⁸ R⁹ 1 PO(OH)₂ H

2 PO(OH)₂ H

3 PO(OH)₂ H

4 PO(OH)₂ H

5 PO(OH)₂ H

6 PO(OH)₂ H

7 PO(OH)₂ —CH₃

8 PO(OH)₂ —CH₃

9 PO(OH)₂ —CH₃

10  PO(OH)₂ —CH₃

11  PO(OH)₂ —CH₃

12  PO(OH)₂ —CH₃

TABLE 11 (I-C1)

No. R¹ R⁸ R⁹ 1 COOH H

2 COOH H

3 COOH H

4 COOH H

5 COOH H

6 COOH H

7 COOH —CH₃

8 COOH —CH₃

9 COOH —CH₃

10  COOH —CH₃

11  COOH —CH₃

12  COOH —CH₃

TABLE 12 (I-C2)

No. R¹ R⁸ R⁹ 1 CONHOH H

2 CONHOH H

3 CONHOH H

4 CONHOH H

5 CONHOH H

6 CONHOH H

7 CONHOH —CH₃

8 CONHOH —CH₃

9 CONHOH —CH₃

10  CONHOH —CH₃

11  CONHOH —CH₃

12  CONHOH —CH₃

TABLE 13 (I-C3)

No. R¹ R⁸ R⁹ 1 CONHNH₂ H

2 CONHNH₂ H

3 CONHNH₂ H

4 CONHNH₂ H

5 CONHNH₂ H

6 CONHNH₂ H

7 CONHNH₂ —CH₃

8 CONHNH₂ —CH₃

9 CONHNH₂ —CH₃

10  CONHNH₂ —CH₃

11  CONHNH₂ —CH₃

12  CONHNH₂ —CH₃

TABLE 14 (I-C4)

No. R¹ R⁸ R⁹ 1 CH₂—SH H

2 CH₂—SH H

3 CH₂—SH H

4 CH₂—SH H

5 CH₂—SH H

6 CH₂—SH H

7 CH₂—SH —CH₃

8 CH₂—SH —CH₃

9 CH₂—SH —CH₃

10  CH₂—SH —CH₃

11  CH₂—SH —CH₃

12  CH₂—SH —CH₃

TABLE 15 (I-C5)

No. R¹ R⁸ R⁹ 1 PO(OH)₂ H

2 PO(OH)₂ H

3 PO(OH)₂ H

4 PO(OH)₂ H

5 PO(OH)₂ H

6 PO(OH)₂ H

7 PO(OH)₂ —CH₃

8 PO(OH)₂ —CH₃

9 PO(OH)₂ —CH₃

10  PO(OH)₂ —CH₃

11  PO(OH)₂ —CH₃

12  PO(OH)₂ —CH₃

TABLE 16 (I-D1)

No. R¹ R⁸ R⁹ 1 COOH H

2 COOH H

3 COOH H

4 COOH H

5 COOH H

6 COOH H

7 COOH —CH₃

8 COOH —CH₃

9 COOH —CH₃

10  COOH —CH₃

11  COOH —CH₃

12  COOH —CH₃

TABLE 17 (I-D2)

No. R¹ R⁸ R⁹ 1 CONHOH H

2 CONHOH H

3 CONHOH H

4 CONHOH H

5 CONHOH H

6 CONHOH H

7 CONHOH —CH₃

8 CONHOH —CH₃

9 CONHOH —CH₃

10  CONHOH —CH₃

11  CONHOH —CH₃

12  CONHOH —CH₃

TABLE 18 (I-D3)

No. R¹ R⁸ R⁹ 1 CONHNH₂ H

2 CONHNH₂ H

3 CONHNH₂ H

4 CONHNH₂ H

5 CONHNH₂ H

6 CONHNH₂ H

7 CONHNH₂ —CH₃

8 CONHNH₂ —CH₃

9 CONHNH₂ —CH₃

10  CONHNH₂ —CH₃

11  CONHNH₂ —CH₃

12  CONHNH₂ —CH₃

TABLE 19 (I-D4)

No. R¹ R⁸ R⁹ 1 CH₂—SH H

2 CH₂—SH H

3 CH₂—SH H

4 CH₂—SH H

5 CH₂—SH H

6 CH₂—SH H

7 CH₂—SH —CH₃

8 CH₂—SH —CH₃

9 CH₂—SH —CH₃

10  CH₂—SH —CH₃

11  CH₂—SH —CH₃

12  CH₂—SH —CH₃

TABLE 20 (I-D5)

No. R¹ R⁸ R⁹ 1 PO(OH)₂ H

2 PO(OH)₂ H

3 PO(OH)₂ H

4 PO(OH)₂ H

5 PO(OH)₂ H

6 PO(OH)₂ H

7 PO(OH)₂ —CH₃

8 PO(OH)₂ —CH₃

9 PO(OH)₂ —CH₃

10  PO(OH)₂ —CH₃

11  PO(OH)₂ —CH₃

12  PO(OH)₂ —CH₃

TABLE 21 (I-E1)

No. R¹ R⁸ R⁹ 1 COOH H

2 COOH H

3 COOH H

4 COOH H

5 COOH H

6 COOH H

7 COOH —CH₃

8 COOH —CH₃

9 COOH —CH₃

10  COOH —CH₃

11  COOH —CH₃

12  COOH —CH₃

TABLE 22 (I-E2)

No. R¹ R⁸ R⁹ 1 CONHOH H

2 CONHOH H

3 CONHOH H

4 CONHOH H

5 CONHOH H

6 CONHOH H

7 CONHOH —CH₃

8 CONHOH —CH₃

9 CONHOH —CH₃

10  CONHOH —CH₃

11  CONHOH —CH₃

12  CONHOH —CH₃

TABLE 23 (I-E3)

No. R¹ R⁸ R⁹ 1 CONHNH₂ H

2 CONHNH₂ H

3 CONHNH₂ H

4 CONHNH₂ H

5 CONHNH₂ H

6 CONHNH₂ H

7 CONHNH₂ —CH₃

8 CONHNH₂ —CH₃

9 CONHNH₂ —CH₃

10  CONHNH₂ —CH₃

11  CONHNH₂ —CH₃

12  CONHNH₂ —CH₃

TABLE 24 (I-E4)

No. R¹ R⁸ R⁹ 1 CH₂—SH H

2 CH₂—SH H

3 CH₂—SH H

4 CH₂—SH H

5 CH₂—SH H

6 CH₂—SH H

7 CH₂—SH —CH₃

8 CH₂—SH —CH₃

9 CH₂—SH —CH₃

10  CH₂—SH —CH₃

11  CH₂—SH —CH₃

12  CH₂—SH —CH₃

TABLE 25 (I-E5)

No. R¹ R⁸ R⁹ 1 PO(OH)₂ H

2 PO(OH)₂ H

3 PO(OH)₂ H

4 PO(OH)₂ H

5 PO(OH)₂ H

6 PO(OH)₂ H

7 PO(OH)₂ —CH₃

8 PO(OH)₂ —CH₃

9 PO(OH)₂ —CH₃

10  PO(OH)₂ —CH₃

11  PO(OH)₂ —CH₃

12  PO(OH)₂ —CH₃

[Process for the Preparation]

The compounds of the present invention of the formula (I), may beprepared by following methods or the methods described in the Examples.

[1] The compound in which R¹ is —COOR¹⁰, that is the compound of theformula (I-1)

wherein all the symbols are as hereinbefore defined; may be prepared byfollowing methods (a)-(c).

(a) The compound in which —COOR¹⁰ of R¹ is not —COOH, and all of R², R³,R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are not hydroxy, amino, or a group including—COOH, hydroxy or amino, that is the compound of the formula (I-1a):

wherein R^(10-1a) is C1-8 alkyl, C2-8 alkenyl, phenyl, C1-8 alkylsubstituted by phenyl or C1-8 alkoxy, oxycarbonyl substituted by phenyl,benzyl or C1-8 alkyl, each of R^(2-1a), R^(3-1a), R^(4-1a), R^(5-1a),R^(6-1a), R^(7-1a), R^(8-1a) and R^(9-1a) is the a same meaning as R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹, with the proviso that, all of R^(2-1a),R^(3-1a), R^(4-1a), R^(5-1a), R^(6-1a), R^(7-1a), R^(8-1a), R^(9-1a) arenot hydroxy, amino, or group including —COOH, hydroxy or amino, and theother symbols are as hereinbefore defined;

may be prepared by amidation of the compound of the formula (II):

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (III):

wherein all the symbols are as hereinbefore defined.

The method of amidation of the compound of the formula (II) with thecompound of the formula (III) is known. It includes the method

(1) via an acyl halide,

(2) via a mixed acid anhydride,

(3) using a condensing agent.

These methods are explained as follows.

(1) The method via an acyl halide, for example, may be carried out in anorganic solvent (e.g. chloroform, methylene chloride, diethyl ether ortetrahydrofuran) or without a solvent, using an acyl halide (e.g. oxalylchloride or thionyl chloride etc.) at −20° C. to reflux temperature, andthe obtained acyl halide derivative may be reacted with an amine in anorganic solvent (e.g. chloroform, methylene chloride, diethyl ether ortetrahydrofuran) in the presence of a tertiary amine (e.g. pyridine,triethyl amine, dimethyl aniline or dimethylaminopyridine) at 0-40° C.

(2) The method via a mixed acid anhydride may be carried out, forexample, by reacting a carboxylic acid with an acyl halide (e.g.pivaloyl chloride, tosyl chloride or mesyl chloride) or an acidderivative (e.g. ethyl chloroformate or isobutyl chloroformate) in anorganic solvent (e.g. chloroform, methylene chloride, diethyl ether ortetrahydrofuran) or without a solvent, in the presence of a tertiaryamine (e.g. pyridine, triethylamine, dimethylaniline ordimethylaminopyridine) at 0-40° C., and the obtained mixed acidanhydride derivative may be reacted with a corresponding amine in anorganic solvent (e.g. chloroform, methylene chloride, diethyl ether ortetrahydrofuran) at 0-40° C.

(3) The method using a condensing agent (e.g. 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propl]carbodiimide(EDC), 1,1′-carbonyldiimidazole (CDI) or 2-chloro-1-methylpyridiniumiodide) maybe carried out, for example, by reacting a carboxylic acidwith an amine in an organic solvent (e.g. chloroform, methylenechloride, dimethylformamide, diethyl ether or tetrahydrofuran) orwithout a solvent, optionally in the presence of a tertiary amine (e.g.pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) usinga condensing agent, and optionally in the presence of1-hydroxybenzotriazole (HOBt) at 0-40° C.

The reaction described in (1), (2) and (3) may be carried out under aninert gas (e.g. argon, nitrogen) to avoid water in order to obtain apreferable result.

Besides, a different ester of the formula (I-1a) may be prepared bysubjecting the compound of the formula (I-1aa)

wherein all the symbols are as hereinbefore defined;

that was obtained by deprotection under alkaline conditions,deprotection under acidic conditions, hydrogenelysis, or deprotection ofallyl ester from the compound of the formula (I-1a); to esterificationreaction.

The esterification reaction is known, for example, it may be carried outin organic solvent (e.g. acetone, acetonitrile, DMF), in the presence ofalkali carbonate (e.g. potassium carbonate, sodium carbonate, cesiumcarbonate), using a catalyst (e.g. sodium iodide) or without a catalyst,at 0-100° C.

Further, the compound of the formula (I-1a) may be also prepared byreacting the compound of the formula (I-1a) in which R^(8-1a) ishydrogen, that is the compound of the formula (I-1ab)

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (XIII)

X—R^(8-1ab)  (XIII)

wherein X is halogen atoms, R^(8-1ab) is the same meaning as R^(8-1a),with the proviso that it is not represented hydrogen, and by reactingthe compound of the formula (I-1a) in which R^(2-1a) is hydrogen, thatis the compound of the formula (I-1ac)

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (XIV)

X—R^(2-1a)  (XIV)

wherein all the symbols are as hereinbefore defined.

Furthermore, the compound of the formula (I-1a) maybe also prepared byreacting the compound of the formula (I-1ac) in which R^(8-1a) ishydrogen, with the compound of the formula (XIV) and then the compoundof the formula (XIII)

X—R^(8-1ab)  (XIII)

wherein all the symbols are as hereinbefore defined.

The reaction of the compound of the formula (I-1lab) and the compound ofthe formula (XIII), and the compound prepared by reacting the compoundin which R^(8-1a) is hydrogen in the compound of the formula (I-1ac)with the compound of the formula (XIV), and the compound of the formula(XIII), is known, for example, may be carried out in an organic solvent(e.g. THF), in the presence of a base (e.g. sodium hydroxide), at−20-50° C.

The reaction of the compound of the formula (I-1ac) and the compound ofthe formula (XIV), for example, may be carried out in an organic solvent(e.g. THF, ethyleneglycol dimethyl ether), in the presence of a base(e.g. lithium bis (trimethylsilyl) amide, lithium diisopropylamide),adding an addition (e.g. 1,3-dimethyl-2-imidazolidinone,hexamethylphospholamide) or without an addition, at −78° C.

(b) The compound in which —COOR¹⁰ of R¹ is not —COOH, and at least oneof R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is hydroxy, amino, or a groupincluding —COOH, hydroxy or amino, that is the compound of the formula(I-1b):

wherein each of R^(2-1b), R^(3-1b), R^(4-1b), R^(5-1b), R^(6-1b),R^(7-1b), R^(8-1b), R^(9-1b) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, at least one of R^(2-1b),R^(3-1b), R^(4-1b), R^(5-1b), R^(6-1b), R^(7-1b), R^(8-1b), R^(9-1b) ishydroxy, amino, or a group including —COOH, hydroxy or amino, and theother symbols are as hereinbefore defined;

may be prepared by deprotection under alkaline conditions, deprotectionunder acidic conditions, deprotection of a silyl group or hydrogenolysisof the compound having protected hydroxy or amino, or groups includingprotected —COOH, hydroxy or amino in the compound of the formula (I-1a),that is the compound of the formula (I-1a1):

wherein each of R^(2-1a1), R^(3-1a1), R^(4-1a1, R) ^(5-1a1), R^(6-1a1),R^(7-1a1), R^(8-1a1), R^(9-1a1) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, at least one of R^(2-1a1),R^(3-1a1), R^(4-1a1), R^(5-1a1), R^(6-1a1), R^(7-1a1), R^(8-1a1),R^(9-1a1) is protected hydroxy (e.g. protected by methoxymethyl,ethoxymethyl, methoxyethyl, tetrahydropyranyl, t-butyldimethylsilyl,acetyl, benzyl), protected amino (e.g. protected by benzyloxycarboyl,t-butoxycarbonyl, trifluoroacetyl), or a group including protected —COOH(e.g. protected by methyl, ethyl, t-butyl and benzyl), protected hydroxyor protected amino, and the other symbols are as hereinbefore defined.

Deprotection under alkaline conditions is known, for example, it may becarried out in an organic solvent (e.g. methanol, tetrahydrofuran ordioxane), using an alkali metal hydroxide (e.g. sodium hydroxide,potassium hydroxide or lithium hydroxide), an alkaline earth metalhydroxide (e.g. barium hydroxide or calcium hydroxide) or a carbonate(e.g. sodium carbonate or potassium carbonate), an aqueous solutionthereof or mixture thereof at 0-40° C.

Deprotection under acidic conditions is known, for example, it may becarried out in an organic solvent (e.g. methylene chloride, chloroform,dioxane, ethyl acetate, anisole), using an organic acid (e.g. aceticacid, trifluoroacetic acid, methanesulfonic acid or trimethylsilyliodide), or an inorganic acid (e.g. hydrochloric acid or sulfuric acid)or a mixture thereof (e.g. hydrogen bromide in acetic acid) at 0-100° C.

Deprotection of a silyl group is known, for example, it may be carriedout in a water miscible organic solvent (e.g. tetrahydrofuran oracetonitrile), using tetrabutylammonium fluoride at 0-40° C.

Hydrogenolysis is known, for example, it may be carried out in a solvent[e.g. ether (such as tetrahydrofuran, dioxane, dimethoxyethane ordiethyl ether), alcohol (such as methanol or ethanol), benzene (such asbenzene or toluene), ketone (such as acetone or methyl ethyl ketone),nitrile (such as acetonitrile), amide (such as dimethylformamide),water, ethyl acetate, acetic acid or two more mixture thereof], in thepresence of a catalyst (e.g. palladium on carbon, palladium black,palladium, palladium hydroxide, platinum dioxide, nickel orRaney-nickel), optionally in the presence of an inorganic acid (e.g.hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid ortetrafluoroboric acid) or an organic acid (e.g. acetic acid,p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid or formicacid), at ordinary or elevated pressure of hydrogen gas or ammoniumformate at 0-200° C. It has no difficulty in using a salt of acid, whenit is carried out using an acid.

(c) The compound in which —COOR¹⁰ of R¹ is —COOH, that is the compoundof the formula (I-1c):

wherein all the symbols are the same meaning as hereinbefore defined;

may be prepared by deprotection under alkaline conditions, deprotectionunder acidic conditions, hydrogenolysis or deprotection of allyl esterof the above compounds of the formula (I-1a) and the formula (I-1b).

The reaction of deprotection under alkaline conditions, deprotectionunder acidic conditions and hydrogenolysis are known and they may becarried out by the same method as hereinbefore described.

The reaction of deprotection of allyl ester is known, for example, itmay be carried out in an organic solvent [e.g. ether (such as THF,dioxane, dimethoxyethane or diethyl ether), alcohol (such as methanol orethanol), benzene (such as benzene or toluene), ketone (such as acetoneor methyl ethyl ketone), nitrile (such as acetonitrile), amide (such asDMF)], in the presence of a catalyst (e.g. palladium, such astetrakis(triphenylphosphin)palladium(0)), in the presence of secondaryamine (e.g. morphorine, piperadine) or/and trimethylsilyl halide, at0-100° C.

[2] In the compounds of the present invention of the formula (I), thecompound in which R¹ is —CONHOR¹⁰ or —CONHNHR¹⁰, that is the compound ofthe formula (I-2):

wherein R²⁻¹ is —CONHOR¹⁰ or —CONHNHR¹⁰, and the other symbols are ashereinbefore defined; may be prepared by following methods (a) and (b).

(a) The compound in which R¹ is —CONHOR¹⁰ or —CONHNHR¹⁰, and all of R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are not a group including —COOH, that isthe compound of the formula (I-2a):

wherein each of R^(2-2a), R^(3-2a), R^(4-2a), R^(5-2a), R^(6-2a),R^(7-2a), R^(8-2a), R^(9-2a) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, all of R^(2-2a), R^(3-2a),R^(4-2a), R^(5-2a), R^(6-2a), R^(7-2a), R^(8-2a), R^(9-2a) are not agroup including —COOH, and the other symbols are as hereinbeforedefined;

may be prepared by amidation of the compound of the above formula (I-1)in which R¹ is COOH, and all of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, are nota group including —COOH, that is the compound of the formula (I-1d):

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (IV):

H₂N—OR¹⁰  (IV)

wherein R¹⁰ is as hereinbefore defined;

or the compound of the formula (V):

H₂N—NHR¹⁰  (V)

wherein R¹⁰ is the same meaning as hereinbefore defined;

if necessary, continuously, by deprotection under alkaline conditionsand/or deprotection under acidic conditions and/or hydrogenolysis.

This reaction of amidation, the reactions of deprotection under alkalineconditions, deprotection under acidic conditions and hydrogenolysis areknown, and may be carried out by the same method as hereinbeforedescribed.

(b) The compound in which R¹ is —CONHOR¹⁰ or —CONHNHR¹⁰, and at leastone of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is a group including —COOH,that is the compound of the formula (I-2b)

wherein each of R^(2-2b), R^(3-2b), R^(4-2b), R^(5-2b), R^(6-2b),R^(7-2b), R^(8-2b), R^(9-2b) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, at least one of R^(2-2b),R^(3-2b), R^(4-2b), R^(5-2b), R^(6-2b), R^(7-2b), R^(8-2b), R^(9-2b) isa group including —COOH, and the other symbols are as hereinbeforedefined;

may be prepared by deprotection under alkaline conditions, deprotectionunder acidic conditions or hydrogenolysis of the compound of the aboveformula (I-2a) having a group including protected —COOH, that is thecompound of the formula (I-2a1)

wherein each of R^(2-2a1), R^(3-2a1), R^(4-2a1), R^(5-2a1), R^(6-2a1),R^(7-2a1), R^(8-2a1), R^(9-2a1) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, at least one of R^(2-2a1),R^(3-2a1), R^(4-2a1), R^(5-2a1), R^(6-2a1), R^(7-2a1), R^(8-2a1),R^(9-2a1) is a group including protected —COOH (e.g. protected bymethyl, ethyl, t-butyl and benzyl), and the other symbols are ashereinbefore defined.

The reactions of deprotection under alkaline conditions, deprotectionunder acidic conditions and hydrogenolysis are known, and may be carriedout by the same method as hereinbefore described.

[3] In the compounds of the present invention of the formula (I), thecompound in which R¹ is —(CH₂)_(n)SR⁵⁰, that is the compound of theformula (I-3)

wherein R¹⁻³ is —(CH₂)_(n)SR⁵⁰, and the other symbols are ashereinbefore defined;

 may be prepared by following methods (a) and (b).

(a) The compound in which R¹ is —(CH₂)_(n)SR⁵⁰, and all of R², R³, R⁴,R⁵, R⁶, R⁷, R⁸ and R⁹ are not hydroxy, amino, or a group including—COOH, hydroxy or amino, that is the compound of the formula (I-3a)

wherein each of R^(2-3a), R^(3-3a), R^(4-3a), R^(5-3a), R^(6-3a),R^(7-3a), R^(8-3a), R^(9-3a) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, all of R^(2-3a), R^(3-3a),R^(4-3a), R^(5-3a), R^(6-3a), R^(7-3a), R^(8-3a), R^(9-3a) are nothydroxy, amino, or a group including —COOH, hydroxy or amino, and theother symbols are as hereinbefore defined;

may be prepared by reaction of the compound of the formula (VI)

wherein X is halogen atoms and the other symbols are as hereinbeforedefined;

with the compound of the formula (VII)

R⁵⁰¹SK  (VII)

wherein R⁵⁰¹ is C1-8 alkyl, —COR⁵², —SR⁵³¹, in which R⁵³¹ is C1-8 alkylor phenyl.

The compound of the formula (I-3a) in which R⁵⁰ is hydrogen or —SH maybe prepared by a reaction of deprotection of the compound obtained bythe above method.

The above method is known, for example, it may be carried out byrefluxing in an organic solvent (e.g. acetone, tetrahydrofuran).

The continuous reaction, that is deprotection is known, for example, itmay be carried out in an organic solvent (e.g. methanol, tetrahydrofuranor dioxane), using an alkali metal hydroxide (e.g. sodium hydroxide,potassium hydroxide or lithium hydroxide), an alkaline earth metalhydroxide (e.g. barium hydroxide or calcium hydroxide) or a carbonate(e.g. sodium carbonate or potassium carbonate), an aqueous solutionthereof or mixture thereof at 0-40° C.

(b) The compound in which R¹ is —(CH₂)_(n)SR⁵⁰, and at least one of R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is a group including —COOH, hydroxy or agroup including it, amino or a group including it, that is the compoundof the formula (I-3b)

wherein each of R^(2-3b), R^(3-3b), R^(4-3b), R^(5-3b), R^(6-3b),R^(7-3b), R^(8-3b), R^(9-3b) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, at least one of R^(2-3b),R^(3-3b), R^(4-3b), R^(5-3b), R^(6-3b), R^(7-3b), R^(8-3b), R^(9-3b) ishydroxy, amino, or a group including —COOH, hydroxy or amino, and theother symbols are as hereinbefore defined;

may be prepared by deprotection under alkaline conditions, deprotectionunder acidic conditions or hydrogenolysis of the compound of the aboveformula (I-3a) having protected hydroxy, protected amino, or a groupincluding protected —COOH, hydroxy or amino, that is the compound of theformula (I-3a1)

wherein each of R^(2-3a1), R^(3-3a1), R^(4-3a1), R^(5-3a1), R^(6-3a1),R^(7-3a1), R^(8-3a1), R^(9-3a1) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, at least one of R^(2-3a1),R^(3-3a1), R^(4-3a1), R^(5-3a1), R^(6-3a1), R^(7-3a1), R^(8-3a1),R^(9-3a1) is protected hydroxy (e.g. protected by methoxymethyl,ethyoxymethyl, methoxyethyl, tetrahydropyranyl, t-butyldimethylsilyl,acetyl or benzyl), or protected amino (e.g. protected bybenzyloxycarboyl, t-butoxycarbonyl, trifluoroacetyl), or a groupincluding protected —COOH (e.g. protected by methyl, ethyl, t-butyl andbenzyl), protected hydroxy or protected amino, and the other symbols areas hereinbefore defined.

The reactions of deprotection under alkaline conditions, deprotectionunder acidic conditions and hydrogenolysis are known, and may be carriedout by the same method as hereinbefore described.

[4] In the compounds of the present invention of the formula (I) , thecompound in which R¹ is —Y—PO(OR⁵¹)₂, that is the compound of theformula (I-4)

wherein R¹⁻⁴ is —Y—PO(OR⁵¹)₂, and the other symbols are as hereinbeforedefined;

 may be prepared by following methods (a)-(d).

(a) The compound in which R¹ is —Y¹—PO(OR⁵¹)₂, in which Y¹ is —O— andthe other symbols are as hereinbefore defined; and all of R², R³, R⁴,R⁵, R⁶, R⁷, R⁸ and R⁹ are not hydroxy, amino, or a group including—COOH, hydroxy or amino, that is the compound of the formula (I-4a)

wherein each of R^(2-4a), R^(3-4a), R^(4-4a), R^(5-4a), R^(6-4a),R^(7-4a), R^(8-4a), R^(9-4a) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, all of R^(2-4a), R^(3-4a),R^(4-4a), R^(5-4a), R^(6-4a), R^(7-4a), R^(8-4a), R^(9-4a) are nothydroxy, amino, or a group including —COOH, hydroxy or amino, and theother symbols are as hereinbefore defined;

may be prepared by reaction of the compound of the formula (VIII)

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (IX)

wherein R⁵¹¹ is C1-8 alkyl, phenyl or a known protecting group ofphosphoric acid and the other symbols are as hereinbefore defined;

when using the compound of the formula (IX) in which R⁵¹¹ is protectedphosphoric acid, continuously, by deprotection.

The above reaction is known, for example, it may be carried out in anorganic solvent (e.g. pyridine) at 0-40° C.

The reaction of deprotection of phosphoric acid is known, for example,it may be carried out in an organic solvent (e.g. pyridine), using zincacetate at 0-40° C.

(b) The compound in which R¹ is —Y¹—PO(OR⁵¹)₂, and at least one of R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is hydroxy, amino, or a group including—COOH, hydroxy or amino, that is the compound of the formula (I-4b)

wherein each of R^(2-4b), R^(3-4b), R^(4-4b), R^(5-4b), R^(6-4b),R^(7-4b), R^(8-4b), R^(9-4b) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, at least one of R^(2-4b),R^(3-4b), R^(4-4b), R^(5-4b), R^(6-4b), R^(7-4b), R^(8-4b), R^(9-4b) ishydroxy, amino, or a group including —COOH, hydroxy or amino, and theother symbols are as hereinbefore defined;

may be prepared by deprotection under alkaline conditions, deprotectionunder acidic conditions or hydrogenolysis of the compound of the aboveformula (I-4a) having a group including protected hydroxy, protectedamino, or a group including protected —COOH, protected hydroxy orprotected amino, that is the compound of the formula (I-4a1)

wherein each of R^(2-4a1), R^(3-4a1), R^(4-4a1), R^(5-4a1), R^(6-4a1),R^(7-4a1), R^(8-4a1), R^(9-4a1) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, at least one of R^(2-4a1),R^(3-4a1), R^(4-4a1), R^(5-4a1), R^(6-4a1), R^(7-4a1), R^(8-4a1),R^(9-4a1) is protected hydroxy (e.g. protected by methoxymethyl,ethoxymethyl, methoxyethyl, tetrahydropyranyl, t-butyldimethylsilyl,acetyl, benzyl), protected amino (e.g. protected by benzyloxycarboyl,t-butoxycarbonyl, trifluoroacetyl), or a group including protected —COOH(e.g. protected by methyl, ethyl, t-butyl and benzyl), protected hydroxyor protected amino, and the other symbols are as hereinbefore defined.

The reactions of deprotection under alkaline conditions, deprotectionunder acidic conditions and hydrogenolysis are known, and may be carriedout by the same method as hereinbefore described.

(c) The compound in which R¹ is —Y²—PO(OR⁵¹)₂, in which Y² is a singlebond or —CH₂— and the other symbols are as hereinbefore defined; and allof R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are not hydroxy, amino, or a groupincluding —COOH, hydroxy or amino, that is the compound of the formula(I-4c)

wherein each of R^(2-4c), R^(3-4c), R^(4-4c), R^(5-4c), R^(6-4c),R^(7-4c), R^(8-4c), R^(9-4c) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, all of R^(2-4c), R^(3-4c),R^(4-4c), R^(5-4c), R^(6-4c), R^(7-4c), R^(8-4c), R^(9-4c) are nothydroxy, amino or a group including —COOH, hydroxy or amino, and theother symbols are as hereinbefore defined;

may be prepared by reaction of the compound of the formula (X):

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (XI)

(R⁵¹¹O)₃P  (XI)

or the compound of the formula (XII)

(R⁵¹¹O)₂POK  (XII)

wherein all the symbols are as hereinbefore defined;

when using the compound of the formula (XI) or the compound of theformula (XII) in which R⁵¹¹ is protected phosphoric acid, continuously,by deprotection.

The above reaction is known, for example, it maybe carried out in anorganic solvent (e.g. tetrahydrofuran, dimethylformamide) at 0-120° C.

The reaction of deprotection of phosphoric acid is known, and it may becarried out by the same method as hereinbefore described.

(d) The compound in which R¹ is —Y²—PO(OR⁵¹)₂, and at least one of R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is hydroxy, amino, or a group including—COOH, hydroxy or amino, that is the compound of the formula (I-4d)

wherein each of R^(2-4d), R^(3-4d), R^(4-4d), R^(5-4d), R^(6-4d),R^(7-4d), R^(8-4d), R^(9-4d) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, at least one of R^(2-4d),R^(3-4d), R^(4-4d), R^(5-4d), R^(6-4d), R^(7-4d), R^(8-4d), R^(9-4d) ishydroxy, amino, or a group including —COOH, hydroxy or amino, it, andthe other symbols are as hereinbefore defined; may be prepared bydeprotection under alkaline conditions, deprotection under acidicconditions or hydrogenolysis of the compound of the above formula (I-4c)having protected a group including protected hydroxy, protected amino ora group including protected —COOH, hydroxy or amino, that is thecompound of the formula (I-4c1)

wherein each of R^(2-4c1), R^(3-4c1), R^(4-4c1), R^(5-4c1), R^(6-4c1),R^(7-4c1), R^(8-4c1), R^(9-4c1) is the a same meaning as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, with the proviso that, at least one of R^(2-4c1),R^(3-4c1), R^(4-4c1), R^(5-4c1), R^(6-4c1), R^(7-4c1), R^(8-4c1),R^(9-4c1) is protected hydroxy, protected amino or a group includingprotected —COOH (e.g. protected by methyl, ethyl, t-butyl and benzyl),protected hydroxy or protected amino and the other symbols are ashereinbefore defined.

The reactions of deprotection under alkaline conditions, deprotectionunder acidic conditions and hydrogenolysis are known, and may be carriedout by the same method as hereinbefore described.

The reactions of deprotection in the present invention are a commonreactions of deprotection as will be apparent to those skilled in theart, for example, deprotection under alkaline conditions, deprotectionunder acidic conditions or hydrogenolysis. The desired compound of thepresent invention may be easily prepared using these protecting groups.

As will be apparent to those skilled in the art, methyl, ethyl, t-butylor benzyl may be used protecting groups for carboxyl, but other groups,which may be removed easily and selectively, are also preferred. Forexample, the groups described in T. W. Greene, Protective Groups inOrganic Synthesis, Wiley, N.Y., 1991, may be used.

Methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl or benzylmay be used protecting groups for hydroxy, but other groups, which maybe removed easily and selectively, are also preferred. For example, thegroups described in T. W. Greene, Protective Groups in OrganicSynthesis, Wiley, N.Y., 1991, may be used.

Benzyloxycarbonyl, t-butoxycarbonyl or trifluoroacetyl may be used asprotecting groups for amino, but other groups which may be removedeasily and selectively are also preferred. For example, the groupsdescribed in T. W. Greene, Protective Groups in Organic Synthesis,Wiley, N.Y., 1991, may be used.

The compounds of the formulae (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X) , (XI), (XII), (XIII) and (XIV) are known per se ormay be prepared by known methods.

In each reaction in the present specification, products may be purifiedby conventional techniques. For example, purification may be carried outby distillation at atmospheric or reduced pressure, by high performanceliquid chromatography, by thin layer chromatography or by columnchromatography using silica gel or magnesium silicate, by washing or byrecrystallization. Purification may be carried out after each reaction,or after a series of reactions.

[Pharmacological Activities]

The potency of inhibitory activity against each matrixmetalloproteinases of the compound of the formula (I) was confirmed asbelow.

(1) Inhibitory Activity Against Gelatinase A

Method

The progelatinase A (5 μl; in assay buffer (40 μl)) was purified fromhuman normal skin dermal fibroblasts (HNDF). It was activated by addingthereto 10 mM of p-aminophenylmercuric acetate (APMA) (5 μl) andpreincubating for 1 hour at 37° C.

A mixture of the synthetic substrate(MOCAc-Pro-Leu-Gly-A2pr(Dnp)-Ala-Arg-NH₂) (130 μl; a final concentration13.5 μM) and a solution (20 μl) with or without various concentrationsof the test compound was preincubated for 5 minutes at 37° C.

The solution of activated gelatinase A (50 μl/well) was mixed with themixture and the mixture was incubated for 15 minutes at 37° C. Theenzyme reaction was started. The enzyme activity was represented byincreasing value of fluorescent intensity [Ex=325 nm (Ex)/393 nm (Em)]per 1 minute. Inhibitory activity was represented by inhibitorypercentage (%) per enzyme activity without the test compound.

The result was showed in Table 26.

TABLE 26 Example No. IC₅₀ (μM)  8(6) 0.0017 16(2) 0.0042

(2) Inhibitory Activity Against Collagenase

Method

The procollagenase (5 μl; in assay buffer (105 μl)) was purified fromhuman normal skin dermal fibroblasts (HNDF). It was activated by addingthereto 1 mg/ml Trypsin (45 μl) and preincubating for 1 minute at 37° C.Trypsin was inactivated by addition of 5 mg/ml soybean trypsin inhibitor(SBTI; 50 μl).

A mixture of the synthetic substrate(Ac-Pro-Leu-Gly-[2-mercapto-4-methyl-pentanoyl]-Leu-Gly-OEt) (105 μl; afinal concentration 1.33 mM) and a solution (20 μl) with or withoutvarious concentrations of the test compound was preincubated for 5minutes at 26° C.

The solution of activated enzyme (75 μl /tube, 50 μl) was mixed with themixture and the mixture was incubated for 10 minutes at 26° C.

Absorption at 324 nm was measured 40 points in the course of 10 minutes.Vmax value was determined as measured value in 30 points therein.

The result was showed in Table 27.

TABLE 27 Example No. IC₅₀ (μM) 8 0.014 20(3) 0.0068 21(2) 0.0076

(3) Inhibitory Activity Against Stromelysin

Method

The mixture of human stromelysin (Yagai; 9 volume) and 10 mMp-aminophenylmercury acetate (1 volume) was activated for 20 hours at37° C. A solution of the test compound in dimethylsulfoxide (10 μl) and0.5 mM solution (10 μl) of 10 mM solution of the synthetic substrateNFF-3 (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(DNP)-NH₂., Nva:norvaline, Peptide Laboratory) in dimethylsulfoxide diluted by waterwere added to assay buffer (50 mM tris-HCl, 10 mM CaCl₂, 0.05% Brij35,0.02% NaN₃ (pH7.5)) (150 μl). Furthermore, assay buffer (30 μl) wasadded to the mixture. The mixture was incubated for 10 minutes at 37° C.The reaction was started by addition of a solution of the aboveactivated stromelysin solution (50 μl). The enzyme activity wasrepresented by increasing value of fluorescent intensity [Ex=325 nm(Ex)/393 nm (Em)] per 1 minute. Inhibitory activity was represented byinhibitory percentage (%) per enzyme activity without the test compound.

The result was showed in Table 28.

TABLE 28 Example No. IC₅₀ (μM) 8(6) 0.029 8(7) 0.040

[Toxicity]

The toxicity of the compounds of the present invention is very low andtherefore, the compounds may be considered safe for pharmaceutical use.

[Application for Pharmaceuticals]

Inhibition of matrix metalloproteinase, for example, gelatinase,stromelysin or collagenase, is useful for prevention and/or treatment ofdiseases, for example, rheumatoid diseases, arthrosteitis,osteoarthritis, unusual bone resorption, osteoporosis, periodontitis,interstitial nephritis, arteriosclerosis, pulmonary emphysema,cirrhosis, cornea injury, cornea ulcer, metastasis, invasion or growthof tumor cells, autoimmune disease (Crohn's disease, Sjogren'ssyndrome), disease caused by vascular emigration or infiltration ofleukocytes, arterialization, multiple sclerosis, aorta aneurysm,endometriosis, restenosis after PTCA, unstable angina, acute myocardialinfarction, transient ischemic attack in animals including human beings,especially human beings.

For the purpose above described, the compounds of formulae (I) of thepresent invention and non-toxic salts, acid addition salts or hydratesmay be normally by administered systemically or locally usually by oralor parenteral administration.

The doses to be administered are determined depending upon, for example,age, body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment. In the human adult,the doses per person are generally from 1 mg to 1000 mg, by oraladministration, up to several times per day, and from 0.1 mg to 100 mg,by parenteral administration (preferably intravenous administration), upto several times per day, or continuous administration from 1 to 24hours per day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

The compounds of the present invention may be administered in the formof, for example, solid forms for oral administration, liquid forms fororal administration, injections, liniments or suppositories forparenteral administration.

Solid forms for oral administration include compressed tablets, pills,capsules, dispersible powders, and granules. Capsules include hardcapsules and soft capsules.

In such solid forms, one or more of the active compound(s) maybe admixedwith vehicles (such as lactose, mannitol, glucose, microcrystallinecellulose, starch), binders (such as hydroxypropyl cellulose,polyvinylpyrrolidone or magnesium metasilicate aluminate), disintegrants(such as cellulose calcium glycolate), lubricants (such as magnesiumstearate), stabilizing agents, and solution adjuvants (such as glutamicacid or aspartic acid) and prepared according to methods well known innormal pharmaceutical practice. The solid forms may, if desired, becoated with coating agents (such as sugar, gelatin, hydroxypropylcellulose or hydroxypropylmethyl cellulose phthalate), or be coated withtwo or more films. And further, coating may include containment withincapsules of absorbable materials such as gelatin.

Liquid forms for oral administration include pharmaceutically acceptablesolutions, suspensions and emulsions, syrups and elixirs. In such forms,one or more of the active compound(s) may be dissolved, suspended oremulized into diluent(s) commonly used in the art (such as purifiedwater, ethanol or a mixture thereof). Besides such liquid forms may alsocomprise some additives, such as wetting agents, suspending agents,emulsifying agents, sweetening agents, flavoring agents, aroma,preservative or buffering agent.

Injections for parenteral administration include sterile aqueous,suspensions, emulsions and solid forms which are dissolved or suspendedinto solvent(s) for injection immediately before use. In injections, oneor more of the active compound(s) may be dissolved, suspended oremulized into solvent(s). The solvents may include distilled water forinjection, physiological salt solution, vegetable oil, propylene glycol,polyethylene glycol, alcohol, e.g. ethanol, or a mixture thereof.

Injections may comprise some additives, such as stabilizing agents,solution adjuvants (such as glutamic acid, aspartic acid orPOLYSORBATE80 (registered trade mark)), suspending agents, emulsifyingagents, soothing agent, buffering agents, preservative. They may besterilized at a final step, or may be prepared and compensated accordingto sterile methods. They may also be manufactured in the form of sterilesolid forms which may be dissolved in sterile water or some othersterile diluent(s) for injection immediately before use.

Other forms for parenteral administration include liquids for externaluse, ointments and endermic liniments, inhalations, sprays,suppositories and pessaries for vaginal administration which compriseone or more of the active compound(s) and may be prepared by methodsknown per se. Sprays may comprise additional substances other thandiluents, such as stabilizing agents (such as sodium sulfate), isotonicbuffers (such as sodium chloride, sodium citrate or citric acid). Forpreparation of such sprays, for example, the method described in theU.S. Pat. No. 2,868,691 or U.S. Pat. No. 3,095,355 may be used.

BEST MODE FOR CARRYING OUT THE INVENTION

The following reference examples and examples illustrate the presentinvention, but do not limit the present invention.

The solvents in the parenthesis show the developing or eluting solventsand the ratios of the solvents used are by volume in chromatographicseparations or TLC.

The solvents in the parentheses in NMR show the solvents used inmeasurement.

Reference Example 14(S)-[4-(N-benzyloxycarbonylamino)-5-hydroxy]pentanoic acid methyl ester

To a solution of 4(S)-carboxy-4-(N-benzyloxycarbonylamino)butanoic acidmethyl ester (600 g) and N-hydroxyphtalimide (234 g) in tetrahydrofuran(2.5 L) in the ice-bath, dicyclohexylcarbodiimide (419 g) was added over1 hour. Ice-bath was removed and the solution was stirred for 2 hours.To the reaction mixture, acetic acetate was added. The mixed solutionwas filtered, and the filtrate was concentrated. The obtained solid waswash with ethyl acetate/hexane (1:9). The obtained solid was dissolvedinto tetrahydrofuran (8 L), and in the ice-bath, sodium borohydride (50g) was added, and then tetrahydrofuran/water (1:1, 184 ml) was addedover 4 hours. 2N hydrochloric acid was added to the reaction mixture,and the solution was extracted with ethyl acetate. The extract waswashed with an aqueous solution of sodium bicarbonate and a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated. The obtained solid was washed with ethylacetate/hexane (1:9) to give the title compound (240 g) having thefollowing physical data.

TLC: Rf 0.40 (ethyl acetate:hexane=9:1).

Reference Example 24(S)-[5-ethoxymethoxy-4-(N-benzyloxycarbonylamino)]pentanoic acid methylester

To a solution of the compound prepared in Reference example 1 (320 g) inmethylene chloride (700 ml) in the ice-bath, diisopropylethylamine (596ml) was added. Ethoxymethyl chloride (209 ml) was added to the mixtureover 1 hour. Ice-bath was removed, and then the solution was stirred for2 hours. Ether was added to the reaction mixture. The solution waswashed with water, 1N hydrochloric acid and a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, andconcentrated. The residue was washed with ethyl acetate/hexane (1:9) togive the title compound (358 g) having the following physical data.

TLC: Rf 0.60 (ethyl acetate:hexane=8:2).

Reference Example 3 4(S)-(5-ethoxymethoxy-4-amino)pentanoic acid methylester

To a solution of the compound prepared in Reference example 2 (5.0 g) inmethanol (30 ml), 10% palladium carbon (wet) was added under anatmosphere of argon. The mixture was stirred for 50 minutes under anatmosphere of hydrogen gas. The reaction mixture was filtered, and thefiltrate was concentrated to give the title compound having thefollowing physical data.

TLC: Rf 0.32 (chloroform:methanol=9:1).

EXAMPLE 1 5-ethoxymethoxy-4(S)-[N-(4-iodophenylcarbonyl)amino]pentanoicacid methyl ester

To a solution of the compound prepared in Reference example 3 inmethylene chloride (30 ml), triethylamine (2.1 ml) and 4-iodobenzolychloride (3.54 g) was added under an atmosphere of argon. The mixturewas stirred for 20 minutes. The reaction mixture was extracted withethyl acetate. The extract was dried over anhydrous magnesium sulfateand concentrated. The residue was recrystallized from hexane/ethylacetate (3:2) to give the title compound (3.88 g) having the followingphysical data.

TLC: Rf 0.21 (hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ7.79(2H, d, J=8.6 Hz), 7.52(2H, d, J=8.6 Hz), 6.74(1H, d,J=8.7 Hz), 4.71(1H, d, J=6.6 Hz), 4.68(1H, d, J=6.6 Hz), 4.36-4.25(1H,m), 3.80-3.55(7H, m), 2.56-2.36(2H, m), 2.12-1.93(2H, m), 1.21(3H, t,J=7.1 Hz).

EXAMPLE 2 5-ethoxymethoxy-4(S)-[N-(4-iodophenylcarbonyl)amino]pentanoicacid

To a solution of the compound prepared in Example 1 (3.37 g) inTHF/methanol (20 ml/30 ml), 1N aqueous solution of sodium hydroxide (9ml) was added. The mixture was stirred for 2 hours. The reaction mixturewas neutralized by adding 1N aqueous solution of hydrochloric acid andextracted with ethyl acetate. The solution was 5% aqueous solution ofcitric acid and a saturated aqueous solution of sodium chloride. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated to give the title compound (2.82 g) having the followingphysical data.

NMR (d₆-DMSO): δ12.06(1H, brs), 8.23(1H, d, J=8.4 Hz), 7.84(2H, d, J=8.6Hz), 7.62(2H, d, J=8.6 Hz), 4.59(2H, s), 4.16-4.05(1H, m), 3.54-3.45(4H,m), 2.29-2.20(2H, m), 1.92-1.80(1H, m), 1.77-1.63(1H, m), 1.08(3H, t,J=7.4 Hz).

EXAMPLE 3 5-ethoxymethoxy-4(S)-[N-(4-iodophenylcarbonyl)amino]pentanoicacid allyl ester

To a solution of the compound prepared in Example 2 (4.11 g) indimethylformamide (DMF; 20 ml), potassium carbonate (1.62 g), sodiumiodide (small amount) and allyl bromide (5 ml) were added. The mixturewas vigorously stirred overnight. The reaction mixture was extractedwith ethyl acetate, dried over anhydrous magnesium sulfate andconcentrated. The residue was washed with hexane to give the titlecompound having the following physical data.

NMR (CDCl₃): δ7.78(2H, d, J=8.4 Hz), 7.52(2H, d, J=8.4 Hz), 6.74(1H, d,J=8.7 Hz), 5.92-5.78(1H, m), 5.32-5.16(2H, m), 4.71(1H, d, J=6.9 Hz),4.68(1H, d, J=6.9 Hz), 4.60-4.47(2H, m), 4.36-4.25(1H, m), 3.75(1H, dd,J=10.2 Hz, 3.0 Hz), 3.66-3.56(3H, m), 2.60-2.49(2H, m), 2.16-1.93(2H,m), 1.20(3H, t, J=7.2 Hz).

EXAMPLE 3(1)5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acidallyl ester

The title compounds having the following physical data was obtained bythe same procedure as a series of reaction of Example 1→Example2→Example 3, using 4-nitrobenzoyl chloride in stead of 4-iodobenzoylchloride.

TLC: Rf 0.50 (toluene:ethyl acetate=1:1).

EXAMPLE 4 5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanoicacid allyl ester

To a solution of the compound prepared in Example 3 (2.00 g) in DMF (40ml), copper cyanide (520 mg) was added. The mixture was vigorouslystirred for 3 hours at 50° C. The reaction mixture was cooled, anddiluted with ethyl acetate and water. The solution was filtered, thefiltrate was extracted with ethyl acetate. The organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated to give the title compound(1.12 g) having the following physical data.

NMR (300 MHz, CDCl₃): δ7.90(2H, d, J=8.1 Hz), 7.74(2H, d, J=8.1 Hz),6.96(1H, d, J=8.4 Hz), 5.92-5.79(1H, m), 5.32-5.16(2H, m), 4.72(1H, d,J=6.7 Hz), 4.68(1H, d, J=6.7 Hz), 4.57-4.51(2H, m), 4.37-4.27(1H, m),3.79(1H, dd, J=10.1 Hz, 3.1 Hz), 3.67-3.57(3H, m), 2.62-2.41(2H, m),2.16-1.97(2H, m), 1.20(3H, t, J=7.0 Hz).

EXAMPLE 55-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-methoxymethylpentanoicacid allyl ester

To a solution of the compound prepared in Example 4 (1.87 g) and1,3-dimethyl-2-imidazolidinone (1.7 ml) in tetrahydrofuran (THF; 20 ml),1M lithium bis(trimethylsilyl)amide (11.4 ml; in THF) was dropped at−78° C., and then the mixture was stirred for 30 minutes at sametemperature. Methoxymethyl chloride (1.2 ml) was added to the reactionmixture, and the mixture was stirred for 3 hours. The reaction mixturewas diluted with a saturated aqueous solution of ammonium chloride, andwarmed to room temperature, and then the solution was extracted withethyl acetate. The extract was dried over anhydrous magnesium sulfateand concentrated. The residue was purified by column chromatography(toluene:ethyl acetate=2:1) to give the title compound (1.45 g) havingthe following physical data.

NMR (200 MHz, CDCl₃): δ7.89(2H, d, J=8.8 Hz), 7.73(2H, d, J=8.8 Hz),6.82(1H, d, J=8.8 Hz), 5.90-5.71(1H, m), 5.29-5.11(2H, m), 4.76-4.66(2H,m), 4.63-4.28(3H, m), 3.82-3.74(1H, m), 3.69-3.54(5H, m), 3.34(3H, s),2.86-2.72(1H, m), 2.33-2.12(1H, m), 2.00-1.86(1H, m), 1.20(3H, t, J=7.2Hz).

EXAMPLE 65-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-methoxymethylpentanoicacid

To the solution of the compound prepared in Example 5 (1.45 g) andmorpholine (0.38 ml) in THF (3.6 ml), tetrakis(triphenylphosphine)palladium(0) (20 mg) was added, and the mixture was stirred for 3 hoursat room temperature. The reaction mixture was diluted with ethylacetate, and washed with 1N aqueous solution of hydrochloride and asaturated aqueous solution of sodium chloride. The organic layer wasdried over anhydrous magnesium sulfate and concentrated to give thetitle compound (1.33 g) having the following physical data.

NMR (300 MHz, d₆-DMSO): δ12.19(s, 1H), 8.47(d, J=8.4 Hz, 2H),8.00-7.92(m, 3H), 4.59(s, 2H), 4.24-4.11(m, 1H), 3.54-3.41(m, 6H),3.20(s, 3H), 2.59-2.46(m, 1H), 1.78(t, J=7.2 Hz, 2H), 1.08(t, J=7.0 Hz,3H).

EXAMPLE 6(1)˜6(13)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference example 1→Reference example 2→Reference example3→Example 1→Example 2→Example 3 (→Example 4)→Example 5→Example 6, usinga corresponding compound, for example, using4(R)-carboxy-4-(N-benzyloxycarbonylamino)butanoic acid methyl esterinstead of 4(S)-carboxy-4-(N-benzyloxycarbonylamino)butanoic acid methylester in the Reference example 1, using a corresponding halogen compoundinstead of ethoxy chloride in Reference example 2, using a correspondingacyl chloride instead of 4-iodobenzoyl chloride in the Example 1, usinga corresponding halogen compound instead of methoxymethyl chloride inthe Example 5.

EXAMPLE 6(1)2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid

TLC: Rf 0.36 (chloroform:methanol=9:1)

NMR (300MHz, CDCl₃): δ8.27(d, J=9.0 Hz, 2H), 7.96(d, J=9.0 Hz, 2H),7.09(d, J=9.0 Hz, 1H), 4.72(d, J=6.9 Hz, 1H), 4.68(d, J=6.9 Hz, 1H),4.43-4.32(m, 1H), 3.80(dd, J=10.5, 3.3 Hz, 1H), 3.70-3.50(m, 7H),2.81-2.71(m, 1H), 2.18(ddd, J=14.1, 10.2, 7.5 Hz, 1H), 1.87(dt, J=14.1,4.8 Hz, 1H), 1.21(t, J=6.6 Hz, 3H), 1.20(t, J=7.2 Hz, 3H).

EXAMPLE 6(2)5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR (300MHz, CDCl₃): δ8.25(d, J=8.7 Hz, 2H), 7.94(d, J=8.7 Hz, 2H),7.25(dd, J=5.1, 3.3 Hz, 1H), 7.03-6.92(m, 3H), 4.71(d, J=6.9 Hz, 1H),4.64(d, J=6.9 Hz, 1H), 4.46-4.34(m, 1H), 3.77(dd, J=10.5, 3.3 Hz, 1H),3.64-3.49(m, 3H), 3.04(dd, J=15.0, 6.9 Hz, 1H), 2.92(dd, J=15.0, 6.9 Hz,1H), 2.83-2.72(m, 1H), 2.10(dt, J=14.1, 9.0 Hz, 1H), 1.81(dt, J=14.1,5.4 Hz, 1H), 1.19(t, J=7.2 Hz, 3H).

EXAMPLE 6(3)5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR (200 MHz, CDCl₃): δ8.19 (d, J=8.8 Hz, 2H), 7.91(d, J=8.8 Hz, 2H),7.30-7.18(m, 3H), 6.23(m, 1H), 4.68(d, J=d, J=7.0 Hz, 1H), 4.61(d, J=7.0Hz, 1H), 4.40-4.20(m, 1H), 3.80(dd, J=10.2, 3.0 Hz, 1H), 3.62-3.42(m,3H), 3.00-2.50(m, 3H), 2.12-1.92(m, 1H), 1.84-1.68(m, 1H), 1.16(t, J=7.0Hz, 3H).

EXAMPLE 6(4)2(S)-benzyl-5-pivaloyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid

TLC: Rf 0.54 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.39(s, 1H), 8.70(d, J=1.8 Hz), 8.54(d, J=8.7Hz), 8.31(d, J=9.0 Hz), 8.03(d, J=9.0 Hz), 7.25-7.11(m, 5H),4.38-4.25(m, 1H), 4.10(dd, J=10.8, 4.5 Hz), 4.00(dd, J=10.8, 4.5 Hz),2.82-2.66(m, 2H), 2.42-2.33(m, 1H), 1.72-1.68(m, 2H), 1.03(s, 9H).

EXAMPLE 6(5)5-acetyloxy-2(S)-benzyl-4(s)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid

TLC: Rf 0.42 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ8.21-8.18(m, 2H), 7.91-7.87(m, 2H),7.30-7.16(m, 5H), 6.71(d, J=8.4 Hz), 4.50-4.40(m, 1H), 4.23(dd, J=11.4,5.4 Hz), 4.12(dd, J=11.4, 5.4 Hz), 3.10-3.01(m, 1H), 2.88-2.78(m, 3H),2.06-1.95(m, 1H), 1.99(3, 3H), 1.77-1.69(m, 1H).

EXAMPLE 6(6) 5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxyphenylcarbonyl)amino]pentanoic acid,

TLC: Rf 0.44 (chloroform:methanol=9:1);

NMR (200 MHz, CDCl₃): δ7.75(d, J=8.8 Hz, 2H), 7.42-7.32(m, 2H),7.21-7.13(m, 1H), 7.07-6.99(m, 2H), 6.98(d, J=8.8 Hz, 2H), 6.73(d, J=8.8Hz, 1H), 4.70(d, J=6.6 Hz, 1H), 4.68(d, J=6.6 Hz, 1H), 4.46-4.30(m, 1H),3.76(dd, J=10.2, 3.2 Hz, 1H), 3.70-3.52(m, 5H), 3.39(s, 3H),2.83-2.69(m, 1H), 2.17(ddd, J=14.4, 10.2, 7.0 Hz, 1H), 1.87(ddd, J=14.4,6.2, 4.8 Hz, 1H), 1.21(t, J=7.0 Hz, 3H).

EXAMPLE 6(7)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-(2-furyl)phenylcarbonyl)amino]pentanoicacid

TLC: Rf 0.21 (chloroform:methanol=10:1);

NMR (CDCl₃): δ7.78(2H, d, J=8.5 Hz), 7.68(2H, d, J=8.5 Hz), 7.49(1H, d,J=1.7 Hz), 6.80(1H, d, J=8.8 Hz), 6.73(1H, d, J=3.3 Hz), 6.49(1H, dd,J=1.7, 3.3 Hz), 4.71(1H, d, J=6.6 Hz), 4.68(1H, d, J=6.6 Hz), 4.4(1H,m), 3.71(1H, dd, J=3.3, 10.2 Hz), 3.7-3.55(5H, m), 3.38(3H, s), 2.89(1H,m), 2.17(1H, m), 1.88(1H, m), 1.20(3H, t, J=7.1 Hz).

EXAMPLE 6(8)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-ethoxymethylpentanoicacid

TLC: Rf 0.45 (chloroform:methanol=9:1).

EXAMPLE 6(9)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid

TLC: Rf 0.36 (chloroform:methanol=9:1);

NMR (200 MHz, CDCl₃): δ8.26(d, J=8.6 Hz, 2H), 7.95(d, J=8.6 Hz, 2H),7.05(d, J=8.8 Hz, 1H), 4.72(d, J=6.6 Hz, 1H), 4.68(d, J=6.6 Hz, 1H),4.48-4.30(m, 1H), 3.80(dd, J=10.2, 3.2 Hz, 1H), 3.69-3.53(m, 5H),3.38(s, 3H), 2.83-2.68(m, 1H), 2.16(ddd, J=14.4, 10.0, 7.8 Hz, 1H),1.87(dt, J=14.4, 5.0 Hz, 1H), 1.20(t, J=7.4 Hz, 3H).

EXAMPLE 6(10)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)aminolpentanoicacid

TLC: Rf 0.38 (chloroform:methanol=9:1);

NMR (200 MHz, CDCl₃): δ7.71(d, J=8.8 Hz, 2H), 7.37(d, J=8.8 Hz, 2H),6.83(d, J=8.7 Hz, 1H), 4.70(d, J=7.0 Hz, 1H), 4.68(d, J=7.0 Hz, 1H),4.45-4.28(m, 1H), 3.76(dd, J=10.2, 3.2 Hz, 1H), 3.68-3.52(m, 5H),3.37(s, 3H), 2.82-2.68(m, 1H), 2.13(ddd, J=14.4, 10.0, 7.8 Hz, 1H),1.87(dt, J=14.4, 5.4 Hz, 1H), 1.19(t, J=6.8 Hz, 3H).

EXAMPLE 6(11)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanoicacid

TLC: Rf 0.39 (chloroform:methanol=9:1);

NMR (CD₃OD): δ7.73-7.69(m, 2H), 7.65-7.59(m, 2H), 4.67(s, 2H),4.37-4.28(m, 1H), 3.63-3.53(m, 6H), 3.32(s, 3H), 2.75-2.64(m, 1H),1.96-1.89(m, 2H), 1.15(t, J=7.2 Hz, 3H).

EXAMPLE 6(12)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanoicacid

NMR (300 MHz, d₆-DMSO): δ12.19(1H, s), 8.47(2H, d, J=8.4 Hz),8.00-7.92(3H, m), 4.59(2H, s), 4.24-4.11(1H, m), 3.54-3.41(6H, m),3.20(3H, s), 2.59-2.46(1H, m), 1.78(2H, t, J=7.2 Hz), 1.08(3H, t, J=7.0Hz).

EXAMPLE 6(13)5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanoicacid

TLC: Rf 0.45 (chloroform:methanol=9:1).

EXAMPLE 7N-(1-methoxy-1,1-dimethylmethyl)oxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide

To a solution of the compound prepared in Example 6 (1.32 g) in DMF (15ml), 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride(1.39 g), 1-hydroxybenzotriazole (1.15 g) andN-(1-methoxy-1,1-dimethyloxy)amine (0.8 ml) were added. The mixture wasstirred for 2.5 hours at room temperature. The reaction mixture wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and concentrated to give the title compound having thefollowing physical data.

TLC: Rf 0.31 (chloroform:methanol=19:1);

NMR (300 MHz, d₆-DMSO): δ8.71(s, 1H), 7.94(d, J=8.1 Hz, 2H), 7.15 (d,J=8.4 Hz, 1H), 7.02 (d, J=8.1 Hz, 2H), 4.69(d, J=6.9 Hz, 1H), 4.66(d,J=6.9 Hz, 1H), 4.36-4.22(m, 1H), 3.74(dd, J=10.2, 3.6 Hz, 1H),3.65-3.48(m, 5H), 3.39(s, 3H), 3.22(s, 3H), 3.58-2.47(m, 1H), 2.23(ddd,J=14.4, 11.1, 8.4 Hz, 1H), 1.78(dt, J=14.4, 3.9 Hz, 1H), 1.37(s, 3H),1.26(s, 3H), 1.19(t, J=7.2 Hz, 3H).

EXAMPLE 8N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide

To a solution of the compound prepared in Example 7 in methanol, 1Naqueous solution of hydrochloric acid (10 drops) was added. The mixturewas stirred for 5 minutes at room temperature. The reaction mixture wasextracted with ethyl acetate/toluene, and the extract was concentrated.The residue was recrystallized from isopropyl ether/methanol to give thetitle compound (540 mg) having the following physical data.

TLC: Rf 0.38 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.44(1H, s), 8.75(1H, s), 8.40(1H, d, J=8.7Hz), 7.97(2H, d, J=8.8 Hz), 7.95(2H, d, J=8.8 Hz), 4.58(2H, s),4.16-4.03(1H, m), 3.54-3.28(6H, m), 3.17(3H, s), 2.44-2.33(1H, m),1.80-1.69(1H, m), 1.68-1.55(1H, m), 1.07(3H, t, J=7.1 Hz).

EXAMPLE 8(1)˜8(13)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 7→Example 8, using the compound prepared inExample 6(1)˜6(13).

EXAMPLE 8(1)N-hydroxy-2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide

TLC: Rf 0.29 (chloroform:methanol=19:1);

NMR (200 MHz, d₆-DMSO): δ10.45(s, 1H), 8.75(s, 1H), 8.49(d, J=8.4 Hz,1H), 8.30(d, J=8.8 Hz, 2H), 8.06(d, J=8.8 Hz, 2H), 4.59(s, 2H),4.21-4.00(m, 1H), 3.60-3.28(m, 8H), 2.43-2.26(m, 1H), 1.86-1.50(m, 2H),1.08(t, J=7.0 Hz, 3H), 1.05(t, J=7.0 Hz, 3H).

EXAMPLE 8(2)N-hydroxy-5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.42(s, 1H), 8.72(s, 1H), 8.50(d, J=8.4 Hz,1H), 8.30(d, J=8.7 Hz, 2H), 8.07(d, J=8.7 Hz, 2H), 7.39(dd, J=5.1, 3.9Hz, 1H), 7.07(m, 1H), 6.89(dd, J=5.1, 1.2 Hz, 1H), 4.58(s, 2H),4.28-4.13(m, 1H), 3.51(d, J=5.7 Hz, 2H), 3.45(q, J=7.2 Hz, 2H),2.85-2.68(m, 2H), 2.42-2.28(m, 1H), 1.83-1.60(m, 2H), 1.08(t, J=7.2 Hz,3H).

EXAMPLE 8(3)N-hydroxy-5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR (200 MHz, d₆-DMSO): δ10.45(brs, 1H), 8.75(brs, 1H), 8.51(d, J=8.0Hz, 1H), 8.29(d, J=8.8 Hz, 2H), 8.07(d, J=8.8 Hz, 2H), 7.51(m, 1H),7.35(m, 1H), 6.28(m, 1H), 4.59(s, 2H), 4.30-4.04(m, 1H), 3.62-3.38(m,4H), 2.70-2.45(m, 2H), 2.40-2.20(m, 1H), 1.90-1.58(m, 2H), 1.07(t, J=7.0Hz, 3H).

EXAMPLE 8(4)N-hydroxy-2(S)-benzyl-5-pivaloyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide

TLC: Rf 0.54 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.39(s, 1H), 8.70(d, J=1.8 Hz, 1H), 8.54(d,J=8.7 Hz, 1H), 8.31(d, J=9.0 Hz, 2H), 8.03(d, J=9.0 Hz, 2H),7.25-7.11(m, 5H), 4.38-4.25(m, 1H), 4.10(dd, J=10.8 Hz, 4.5 Hz, 1H),4.00(dd, J=10.8, 7.5 Hz, 1H), 2.82-2.66(m, 2H), 2.42-2.33(m, 1H),1.72-1.68(m, 2H), 1.03(s, 9H).

EXAMPLE 8(5)N-hydroxy-5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide

TLC: Rf 0.62 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.38(s, 1H), 8.65(brs, 1H), 8.57(d, J=8.4 Hz,1H), 8.32-8.28(m, 2H), 8.07-8.03(m, 2H), 7.26-7.11(m, 5H), 4.35-4.23(m,1H), 4.11(dd, J=11.1 Hz, 4.2 Hz, 1H), 4.01(dd, J=11.1, 6.6 Hz, 1H),2.84-2.68(m, 2H), 2.43-2.34(m, 1H), 1.93(s, 3H), 1.80-1.63(m, 2H).

EXAMPLE 8(6)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxyphenylcarbonyl)amino]pentanamide

TLC: Rf 0.28 (chloroform:methanol=19:1);

NMR (300 MHz, d₆-DMSO): δ10.80-10.00(br, 1H), 9.20-8.40(br, 1H), 8.12(d,J=8.4 Hz, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.47-7.38 (m, 2H), 7.21-7.16(m,1H), 7.06(d, J=7.8 Hz, 2H), 7.01(d, J=8.7 Hz, 2H), 4.58(s, 2H),4.16-4.00(m, 1H), 3.57-3.30(m, 6H), 3.17(s, 3H), 2.43-2.34(m, 1H),1.81-1.53(m, 2H), 1.08(t, J=6.9 Hz, 3H).

EXAMPLE 8(7)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-(N-(4-(2-furyl)phenylcarbonyl)amino]pentanamide

TLC: Rf 0.39 (chloroform:methanol:acetic acid:water=100:10:1:1);

NMR (CDCl₃+CD₃OD(a little)): δ7.82(d, J=8.8 Hz, 2H), 7.71(d, J=8.8 Hz,2H), 7.51(m, 1H), 7.17(d, J=8.8 Hz, 1H), 6.75(m, 1H), 6.50(m, 1H),4.71(d, J=6.6 Hz, 1H), 4.67(d, J=6.6 Hz, 1H), 4.31(m, 1H), 3.73-3.46(m,6 H), 3.35(s, 3H), 2.64(m, 1H), 2.11(m, 1H), 1.83(m, 1H), 1.20(t, J=7.1Hz, 3H).

EXAMPLE 8(8)N-hydroxy-5-ethoxymethoxy-2(R)-ethoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide

TLC: Rf 0.50 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.44(1H, s), 8.75(1H, s), 8.40(1H, d, J=8.4Hz), 7.97(2H, d, J=8.4 Hz), 7.94(2H, d, J=8.4 Hz), 4.58(2H, s),4.15-4.04(1H, m), 3.53-3.30(8H, m), 2.37(1H,quint, J=5.3 Hz),1.81-1.70(1H, m), 1.68-1.55(1H, m), 1.07(3H, t, J=7.2 Hz), 1.05(3H, t,J=6.9 Hz).

EXAMPLE 8(9)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanamide

TLC: Rf 0.22 (chloroform:methanol=19:1);

NMR (300 MHz, d₆-DMSO): δ10.60-10.30(brs, 1H), 8.85-8.62(brs, 1H),8.52(d, J=8.7 Hz, 1H), 8.30(d, J=8.7 Hz, 2H), 8.06(d, J=8.7 Hz, 2H),4.59(s, 2H), 4.17-4.03(m, 1H), 3.58-3.28(m, 6H), 3.18(s, 3H),2.44-2.33(m, 1H), 1.81-1.56(m, 2H), 1.08(t, J=6.9 Hz, 3H).

EXAMPLE 8(10)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanamide

TLC: Rf 0.31 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.52-10.35(brs, 1H), 8.84-8.67(brs, 1H),8.22(d, J=8.4 Hz, 1H), 7.85(d, J=8.7 Hz, 2H), 7.52(d, J=8.7 Hz, 2H),4.58(s, 2H), 4.15-4.00(m, 1H), 3.53-3.29(m, 6H), 3.17(s, 3H),2.43-2.32(m, 1H), 1.80-1.54(m, 2H), 1.07(t, J=7.2 Hz, 3H).

EXAMPLE 8(11)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanamide

TLC: Rf 0.31 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.43(s, 1H), 8.74(brs, 1H), 8.21(d, J=8.4 Hz,1H), 7.78(d, J=8.7 Hz, 2H), 7.66(d, J=8.7 Hz, 2H), 4.58(s, 2H),4.13-4.01(m, 1H), 3.50-3.31(m, 6H), 3.16(s, 3H), 2.42-2.12(m, 1H),1.79-1.53(m, 2H), 1.07(t, J=7.2 Hz, 3H).

EXAMPLE 8(12)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanamide

TLC: Rf 0.38 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.44(1H, s), 8.75(1H, s), 8.40(1H, d, J=8.7Hz), 7.97(2H, d, J=8.8 Hz), 7.95(2H, d, J=8.8 Hz), 4.58(2H, s),4.16-4.03(1H, m), 3.54-3.28(6H, m), 3.17(3H, s), 2.44-2.33(1H, m),1.80-1.69(1H, m), 1.68-1.55(1H, m), 1.07(3H, t, J=7.1 Hz).

EXAMPLE 8(13)N-hydroxy-5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanamide

TLC: Rf 0.35 (chloroform:methanol=9:1).

EXAMPLE 9 5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 6, using thecompound prepared in Example 3(1).

TLC: Rf 0.34 (chloroform:methanol=9:1);

NMR (200 MHz, CDCl₃): δ8.28(d, J=8.8 Hz, 2H), 7.97(d, J=8.8 Hz, 2H),7.08(d, J=8.8 Hz, 1H), 4.75(d, J=7. Hz, 1H), 4.70(d, J=7.0 Hz, 1H),4.43-4.27(m, 1H), 3.83(dd, J=10.6, 3.4 Hz, 1H), 3.72-3.57(m, 3H),2.65-2.38(m, 2H), 2.17-1.94(m, 2H), 1.21(t, J=7.0 Hz, 3H).

EXAMPLE 10N-hydroxy-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 7→Example 8, usingthe compound prepared in Example 9.

TLC: Rf 0.34 (chloroform:methanol=9:1);

NMR (200 MHz, d₆-DMSO): δ10.35(s, 1H), 8.57(d, J=8.4 Hz, 1H), 8.31(d,J=8.8 Hz, 2H), 8.07(d, J=8.8 Hz, 2H), 4.60(s, 2H), 4.23-3.99(m, 1H),3.62-3.40(m, 4H), 2.10-1.60(m, 4H), 1.08(t, J=7.0 Hz, 3H).

Reference Example 4 4(S)-(4-amino-5-methoxyethoxymethoxy)pentanoic acidbenzyl ester

To a solution of 4(S)-[5-methoxyethoxymethoxy-4-(N-t-butoxycarbonylamino)]pentanoic acid benzyl ester (8.83 g) that was obtained by thesame procedure as a series of reaction of Reference example 1→Referenceexample 2 (using methoxyethoxymethyl chloride instead of ethoxymethylchloride), using 4(S)-carboxy-4-(N-t-butoxycarbonylamino)butanoic acidbenzyl ester, in methylene chloride (15 ml) in ice-bath, trifluoroaceticacid (15 ml) was added. The mixture was stirred for 80 minutes at 0° C.The reaction mixture was diluted with ethyl acetate/toluene andconcentrated to give the title compound (8.84 g) having the followingphysical data.

TLC: Rf 0.36 (chloroform:methanol=9:1).

EXAMPLE 115-methoxyethoxymethoxy-2(S)-methyl-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanoicacid benzyl ester

To a solution of5-methoxyethoxymethoxy-2(S)-methyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid benzyl ester (820 mg) that was obtained by the same procedure as aseries of reaction of Example 1 (using 4-nitrobenzoyl chloride insteadof 4-iodobenzoyl chloride)→Example 5 (using methyl iodide instead ofmethoxymethyl chloride), using the compound prepared in Referenceexample 4, in THF (15 ml), methyl iodide (0.6 ml) was added. Then 60%sodium hydride (84 mg) was added to the mixture under cooling with ice.The mixture was stirred for 4 hours at 0° C. The reaction mixture waspoured into 5% aqueous solution of citric acid, and extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate andconcentrated to give the title compound having the following physicaldata.

TLC: Rf 0.20 (toluene:methanol=2:1).

EXAMPLE 125-methoxyethoxymethoxy-2(S)-methyl-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanoicacid

To a solution of the compound prepared in Example 11 (319 mg) inTHF/methanol (1:1, 6 ml), 2N aqueous solution of sodium hydroxide (0.6ml) was added. The mixture was stirred for 150 minutes at roomtemperature. The reaction mixture was neutralized by adding 2N aqueoussolution of hydrochloric acid, and extracted with ethyl acetate. Theextract was dried over anhydrous magnesium sulfate and concentrated togive the title compound having the following physical data.

MASS (APCI, neg, 20 V): 397(M−H)⁻.

EXAMPLE 13N-hydroxy-2(S)-methyl-5-methoxyethoxymethoxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide

The following compound having the following physical data was obtainedby the same procedure as a series of reaction of Example 7→Example 8,using the compound prepared in Example 12.

TLC: Rf 0.73 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.50 and 10.43 (s, 1H), 8.90-8.50 (brs, 1H),8.28 and 8.25(d, J=8.8 Hz, 2H), 7.63 and 7.59(d, J=8.8 Hz, 2H),4.83-4.69 and 3.84-3.75(m, 1H), 4.69-4.57(m, 2H), 3.63-3.49(m, 2H),3.48-3.37(m, 4H), 3.24 and 3.22(s, 3H), 2.82 and 2.63(s, 3H), 2.20-2.08and 2.06-1.94(m, 1H), 1.89-1.71(m, 1H), 1.54-1.43 and 1.40-1.29(m, 1H),1.05 and 0.76(d, J=6.6 Hz, 3H).

EXAMPLE 14 5-hydroxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acidallyl ester

To a solution of the compoundprepared in Example 3(1) (5.02 g) in allylalcohol (15 ml), concentrated hydrochloric acid (40 drops) was added,and the mixture was stirred for 30 minutes at 50° C. The reactionmixture was cooled to room temperature, neutralized by adding sodiumbicarbonate and extracted with ethyl acetate. The extract was dried overanhydrous magnesium sulfate to give the title compound having thefollowing physical data.

TLC: Rf 0.35 (toluene:ethyl acetate=1:4);

MASS (APCI, pos, 20 V): 323(M+H)⁺.

Reference Example 55-t-butyldimethylsilyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid allyl ester

To a solution of the compound prepared in Example 14 (4.24 g) in DMF (13ml), imidazole (2.15 g) and t-butyldimethylsilyl chloride (2.38 g) wereadded, and the mixture was stirred for 30 minutes. The reaction mixturewas extracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and concentrated to give the title compound (4.75 g)having the following physical data.

NMR (CDCl₃): δ8.29(2H, d, J=8.9 Hz), 7.93(2H, d, J=8.9 Hz), 6.80(1H, d,J=8.8 Hz), 5.97-5.76(1H, m), 5.34-5.16(2H, m), 4.59-4.52(2H, m),4.28-4.08(1H, m), 3.77-3.72(2H, m), 2.67-2.37(2H, m), 2.17-1.91(2H, m),0.90(9H, s), 0.05(6H, s).

Reference Example 65-t-butyldimethylsilyloxy-2(R)-methoxymethyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid allyl ester

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 5, using thecompound prepared in Reference example 5.

TLC: Rf 0.50 (toluene ethyl acetate=3:1);

NMR (CDCl₃): δ8.29(2H, d, J=8.9 Hz), 7.92(2H, d, J=8.9 Hz), 6.60(1H, d,J=8.1 Hz), 5.88-5.74(1H, m), 5.27-5.13(2H, m), 4.62-4.43(2H, m),4.29-4.17(1H, m), 3.76-3.69(2H, m), 3.68-3.56(2H, m), 3.34(3H, s),2.83-2.73(1H, m), 2.23-2.10(1H, m), 1.96-1.87(1H, m), 0.89(9H, s),0.07(3H, s), 0.04(3H, s).

Reference Example 72(S)-(benzothiophen-3-yl)methyl-5-t-butyldimethylsilyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid allyl ester

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 5→Example 11,using the compound prepared in Reference example 5 and a correspondingcompound.

TLC: Rf 0.54 (toluene:ethyl acetate=4:1);

MASS (APCI, pos, 20 V.): 597(M+H)⁺, 465.

Reference Example 85-t-butyldimethylsilyloxy-2(R)-methoxymethyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 6, using thecompound prepared in Reference example 6.

NMR (d₆-DMSO): δ12.18(1H, s), 8.44(1H, d, J=9.0 Hz), 8.30(2H, d, J=9.0Hz), 8.03(2H, d, J=9.0 Hz), 4.12-3.98(1H, m), 3.63-3.52(2H, m), 3.46(2H,d, J=6.3 Hz), 3.19(3H, s), 2.59-2.48(1H, m), 1.86-1.67(2H, m), 0.82(9H,s), 0.03(6H, s).

EXAMPLE 15N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 7→Example 8, usingthe compound prepared in Reference example 8.

TLC: Rf 0.18 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.43(1H, s), 8.73(1H, brs), 8.35(1H, d, J=8.1Hz), 8.29(2H, d, J=8.7 Hz), 8.07(2H, d, J=8.7 Hz), 4.74(1H, t, J=5.7Hz), 4.02-3.89(1H, m), 3.50-3.31(4H, m), 3.17(3H, s), 2.45-2.34(1H, m),1.82-1.70(1H, m), 1.64-1.51(1H, m).

EXAMPLE 15(1)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-chlorophenylcarbonyl)amino]pentanamide

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Reference example1→Reference example 2→Reference example 3→Example 1 (using4-chiorobenzoyl chloride instead of 4-iodobenzoyl chloride)→Example2→Example 3→Example 14→Reference example 5-→Reference example6→Reference example 8→Example 15, using a corresponding compound.

TLC: Rf 0.20 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.41(1H, s), 8.72(1H, s), 8.05(1H, d, J=8.4Hz), 7.86(2H, d, J=8.4 Hz), 7.51(2H, d, J=8.4 Hz), 4.69(1H, t, J=5.7Hz), 4.00-3.86(1H, m), 3.49-3.27(4H, m), 3.17(3H, s), 2.44-2.30(1H, m),1.82-1.69(1H, m), 1.61-1.49(1H, m).

EXAMPLE 15(2)N-hydroxy-2(S)-(2-benzothiophen-3-yl)methyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Reference example8→Example 15, using the compound prepared in Reference example 7.

TLC: Rf 0.40 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.52 and 10.50(brs, 1H), 8.74(s, 1H), 8.29 and7.95(d, J=8.7 Hz, 2H), 7.96-7.93(m, 1H), 7.87-7.85 and 7.62-7.59(m, 1H),7.69 and 7.47(d, J=8.7 Hz, 2H), 7.37-7.29(m, 3H), 4.99-4.96 and4.88-4.85(m, 1H), 4.81-4.72 and 3.52-3.46(m, 1H), 3.57-3.40 and3.30-3.23(m, 2H), 3.05-3.02 and 2.92-2.87(m, 2H), 2.83 and 2.66(s, 3H),2.49-2.35(m, 1H), 1.87-1.65 and 1.57-1.46(m, 2H).

EXAMPLE 16(1)˜16(5)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 14 Reference example 5→Example 5 (using acorresponding compound instead of methoxymethyl chloride)→Example11→Example 12→Example 7→Example 8, using the compound prepared inExample 1 or a corresponding compound thereof.

EXAMPLE 16(1)N-hydroxy-2(S)-allyl-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide

TLC: Rf 0.25 (chloroform:methanol:water=9:1:0.1);

NMR (300 MHz, d₆-DMSO): δ10.51 and 10.44(s, 1H), 8.76 and 8.70(s, 1H),8.27 and 8.24(d, J=8.1 Hz, 2H), 7.65 and 7.61(d, J=8.1 Hz, 2H),5.81-5.50(m, 1H), 5.08-4.78(m, 3H), 4.64-4.55 and 3.50-3.39(s, 1H),3.54-3.37(m, 2H), 2.81 and 2.62(s, 3H), 2.24-2.18 and 2.16-2.06(m, 1H),2.07-1.88(m, 2H), 1.77-1.52 and 1.44-1.31(m, 2H).

EXAMPLE 16(2)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-bromophenylcarbonyl)amino]pentanamide

TLC: Rf 0.54 (chloroform:methanol:acetic acid=9:1:0.5);

NMR (300 MHz, d₆-DMSO): δ10.50 and 10.45(s, 1H), 8.74 and 8.70(s, 1H),7.66-7.57(m, 2H), 7.39-7.34(m, 2H), 7.30-7.21(m, 2H), 7.19-7.08(m, 3H),4.96 and 4.76(t, J=5.4 Hz, 1H), 4.58-4.37 and 3.68-3.57(m, 1H),3.51-3.41 and 3.34-3.25(m, 2H), 2.77 and 2.63(s, 3H), 2.39-2.25(m, 2H),2.08-1.98 and 1.86-1.77(m, 1H), 1.74-1.44(m, 2H), 1.38-1.13(m, 4H).

EXAMPLE 16(3)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide

TLC: Rf 0.33 (chloroform:methanol:water=9:1:0.1);

NMR (300 MHz, d₆-DMSO): δ10.52 and 10.43(s, 1H), 8.77 and 8.70(s, 1H),8.27 and 8.24 (d, J=8.6 Hz, 2H), 7.65 and 7.61 (d, J=8.6 Hz, 2H),7.30-7.07(m, 5H), 4.99 and 4.81(t, J=5.3 Hz, 1H), 4.64-4.51 and3.53-3.44(m, 1H), 3.52-3.41(m, 2H), 2.81 and 2.61(s, 3H), 2.41-2.32(m,2H), 2.10-2.00 and 1.89-1.78(m, 1H), 1.74-1.47(m, 2H), 1.39-1.22(m, 4H).

EXAMPLE 16(4)N-hydroxy-2(S)-methyl-5-hydroxy-4(S)-[N-methyl-N-[(5-nitro-2-thienyl)carbonyl]amino]pentanamide

TLC: Rf 0.19 (chloroform:methanol:acetic acid=90:10:1);

NMR (300 MHz, d₆-DMSO): δ10.43(brs, 1H), 8.69(brs, 1H), 8.09 and 8.04(d,J=3.9 Hz, 1H), 7.52 and 7.50(d, J=3.9 Hz, 1H), 5.14 and 4.80(brs, 1H),4.58-4.48 and 4.05-3.93(m, 1H), 3.50-3.36(m, 2H), 2.90 and 2.80(s, 3H),2.09-1.95(m, 1H), 1.80-1.64(m, 1H), 1.52-1.35(m, 1H), 1.00-0.82(d, J=6.6Hz, 3H).

EXAMPLE 16(5)N-hydroxy-2(S)-benzyl-5-hydroxy-4(S)-[N-methyl-N-[(5-bromo-2-thienyl)carbonyl]amino]pentanamide

TLC: Rf 0.41 (chloroform:methanol:acetic acid=90:10:1);

NMR (300 MHz, d₆-DMSO): δ10.34(brs, 1H), 8.65(brs, 1H), 7.40-6.98(m,7H), 5.06 and 4.77(brs, 1H), 4.72-4.61 and 4.36-4.21(m, 1H),3.52-3.38(m, 2H), 3.02 and 2.77(s, 3H), 2.76-2.52 and 2.49-2.23(m, 1H),2.21-2.09(m, 1H), 1.76-1.45(m, 2H).

EXAMPLE 17(1)˜17(3)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 1, using trans-2-aminomethylcyclohexanoic acidthat was described in J. Chem. Soc. Perkin Trans I, 2563 (1982), or2-aminocyclohexane carboxylic acid that was described in J. Chem. Soc.Perkin Trans I, 2555 (1982), and a corresponding acyl chloride.

EXAMPLE 17(1) trans-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexanoicacid

TLC: Rf 0.50 (chloroform:methanol=9:1).

EXAMPLE 17(2)trans-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexanoicacid

TLC: Rf 0.55 (chloroform:methanol=9:1).

EXAMPLE 17(3) trans-2-[(4-nitrophenylcarbonyl)amino]cyclohexylaceticacid

EXAMPLE 18(1)˜18(3)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 7→Example 8, using the compound prepared inExample 17(1)˜17(3).

EXAMPLE 18(1)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexane

TLC: Rf 0.38 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.43(s, 1H), 8.57(t, J=5.4 HZ, 1H), 8.28(d,J=8.9 Hz, 2H), 8.05(d, J=8.9 Hz, 2H), 3.20-3.02(m, 2H), 1.95-1.55(m,6H), 1.55-1.30(m, 1H), 1.30-1.02(m, 2H), 1.00-0.80(m, 1H).

EXAMPLE 18(2)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexane

TLC: Rf 0.41 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.42(s, 1H), 9.00-8.35(br, 1H), 8.29(t, J=5.6Hz, 1H), 7.82(d, J=8.9 Hz, 1H), 7.52(d, J=8.9 Hz, 2H), 4.34(s, 2H),3.33(s, 3H, overlap with H2O in DMSO), 3.18-3.02(m, 2H), 1.90-1.55(m,6H), 1.55-1.30(m, 1H), 1.28-1.02(m, 2H), 1.00-0.78(m, 1H).

EXAMPLE 18(3)trans-1-(N-hydroxyaminocarbonylmethyl)-2-[(4-nitrophenylcarbonyl)amino]cyclohexane

TLC: Rf 0.37 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.33(s, 1H), 8.62(d, J=8.7 Hz, 1H), 8.29(d,J=8.7 Hz, 2H), 8.05(d, J=8.7 Hz, 2H), 3.70-3.50(m, 1H, overlap with H₂Oin DMSO), 2.16(dd, J=14.1, 3.3 Hz, 1H), 2.00-1.60(m, 6H), 1.45-0.85(m,4H).

EXAMPLE 19(1)˜19(3)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 5 (using a corresponding compound instead ofmethoxymethyl chloride)→Example 6, using the compound prepared inExample 3(1) or a corresponding compound thereof.

EXAMPLE 19(1)5-ethoxymethoxy-2(R)-(2-propynyloxymethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid

TLC: Rf 0.41 (chloroform:methanol=9:1);

NMR (200 MHz, CDCl₃): δ8.26 (d, J=8.8 Hz, 2H), 7.95 (d, J=8.8 Hz, 2H),7.03(d, J=8.8 Hz, 1H), 4.73(d, J=6.8 Hz, 1H), 4.68(d, J=6.8 Hz, 1H),4.50-4.31(m, 1H), 4.18(d, J=2.2 Hz, 2H), 3.88-3.52(m, 6H), 2.88-2.70(m,1H), 2.46(t, J=2.2 Hz, 1H), 2.17(ddd, J=14.2, 9.6, 8.2 Hz, 1H), 1.92(dt,J=14.2, 5.4 Hz, 1H), 1.20(t, J=7.0 Hz, 3H).

EXAMPLE 19(2)5-ethoxymethoxy-2(R)-(2-propenyloxymethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid

TLC: Rf 0.25 (chloroform:methanol=9:1);

NMR (300 MHz, CDCl₃): δ8.25(d, J=8.7 Hz, 2H), 7.95(d, J=8.7 Hz, 2H),7.06(d, J=9.0 Hz, 1H), 5.94-5.78(m, 1H), 5.31-5.16(m, 2H), 4.73 (d,J=6.6 Hz, 1H), 4.67 (d, J=6.6 Hz, 1H), 4.44-4.32 (m, 1H), 4.02-3.98(m,2H), 3.79(dd, J=10.5, 3.3 Hz, 1H), 3.75-3.55(m, 5H), 2.83-2.73(m, 1H),2.15(ddd, J=14.7, 10.2, 8.1 Hz, 1H), 1.90(dt, J=14.7, 5.4 Hz, 1H),1.20(t, J=7.2 Hz, 3H).

EXAMPLE 19(3)5-ethoxymethoxy-2(R)-(2-propynyloxymethyl)-4(S)-[N-(4-chlorophenylcarbonyl)amino]pentanoicacid

TLC: Rf 0.39 (chloroform:methanol=9:1);

NMR (200 MHz, CDCl₃): δ7.71(d, J=8.8 Hz, 2H), 7.37(d, J=8.8 Hz, 2H),6.80(d, J=8.8 Hz, 1H), 4.71(d, J=6.6 Hz, 1H), 4.68(d, J=6.6 Hz, 1H),4.47-4.30(m, 1H), 4.18(d, J=2.4 Hz, 2H), 3.85-3.68(m, 3H), 3.66-3.52(m,3H), 2.84-2.70(m, 1H), 2.45(t, J=2.4 Hz, 1H), 2.15(ddd, J=14.4, 10.0,7.8 Hz, 1H), 1.92(dt, J=14.4, 5.6 Hz, 1H), 1.20(t, J=7.2 Hz, 3H).

EXAMPLE 20(1)˜20(3)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 7→Example 8, using the compound prepared inExample 19(1)˜19(3).

EXAMPLE 20(1)N-hydroxy-5-ethoxymethoxy-2(R)-(2-propynyloxymethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide

TLC: Rf 0.51 (chloroform:methanol=9:1);

NMR (200 MHz, CD₃OD): δ8.29(d, J=8.8 Hz, 2H), 8.00(d, J=8.8 Hz, 2H),4.68(s, 2H), 4.38-4.20(m, 1H), 4.13(d, J=1.8 Hz, 2H), 3.70-3.48(m, 6H),2.83(t, J=1.8 Hz, 1H), 2.60-2.42(m, 1H), 1.98-1.83(m, 2H), 1.16(t, J=7.2Hz, 3H).

EXAMPLE 20(2)N-hydroxy-5-ethoxymethoxy-2(R)-(2-propenyloxymethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide

TLC: Rf 0.30 (chloroform:methanol=19:1);

NMR (300 MHz, d₆-DMSO): δ10.46(brs, 1H), 8.77(brs, 1H), 8.52(d, J=9.0Hz, 1H), 8.30(d, J=8.7 Hz, 2H), 8.06(d, J=8.7 Hz, 2H), 5.90-5.74(m, 1H),5.27-5.06(m, 2H), 4.59(s, 2H), 4.19-4.02(m, 1H), 3.96-3.80(m, 2H),3.58-3.37(m, 6H), 2.44-2.34(m, 1H), 1.82-1.71(m, 1H), 1.70-1.58(m, 1H),1.08(t, J=6.9 Hz, 3H).

EXAMPLE 20(3)N-hydroxy-5-ethoxymethoxy-2(R)-(2-propynyloxymethyl)-4(S)-[N-(4-chlorophenylcarbonyl)amino]pentanamide

TLC: Rf 0.49 (chloroform:methanol=9:1);

NMR (300 MHz, CD₃OD): δ7.78(d, J=9.0 Hz, 2H), 7.44(d, J=9.0 Hz, 2H),4.67(s, 2H), 4.30-4.20(m, 1H), 4.18-4.03(m, 2H), 3.70-3.50(m, 6H),2.82(t, J=2.7 Hz, 1H), 2.57-2.43(m, 1H), 1.97-1.80(m, 2H), 1.15(t, J=6.9Hz, 3H).

EXAMPLE 21(1)˜21(4)

The following compounds were obtainedby the same procedure as a seriesof reaction of Example 14→Reference example 5→Example 5 (using2-propynyl bromide instead of methoxymethyl chloride)→Example 11→Example12→Example 7→Example 8, using the compound prepared in Example 1 or acorresponding compound thereof.

EXAMPLE 21(1)N-hydroxy-2(S)-(2-propynyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide

TLC: Rf 0.33 (chloroform:methanol:acetic acid=9:1:0.5);

NMR (300 MHz, d₆-DMSO): δ10.56(brs, 1H), 8.87 and 8.82(s, 1H),8.33-8.16(m, 2H), 7.72-7.56(m, 2H), 5.00 and 4.86(t, J=5.6 Hz, 1H),4.61-4.50 and 3.55-3.22 (m, 1H), 3.52-3.25 (m, 2H), 2.85 and 2.69(s,1H), 2.81 and 2.63(s, 3H), 2.38-2.23(m, 2H), 1.91-1.61 and 1.48-1.38(m,2H).

EXAMPLE 21(2)N-hydroxy-2(S)-(2-propynyl)-5-hydroxy-4(S)-[N-methyl-N-(4-bromophenylcarbonyl)amino]pentanamide

TLC: Rf 0.39 (chloroform:methanol:acetic acid=9:1:0.5);

NMR (300 MHz, d₆-DMSO): δ10.59(brs, 1H), 8.83(brs, 1H), 7.63 and 7.58(d,J=8.4 Hz, 2H), 7.36 and 7.32(d, J=8.4 Hz, 2H), 4.94 and 4.80(t, J=4.9Hz, 1H), 4.58-4.47 and 3.63-3.52(m, 1H), 3.51-3.36 and 3.29-3.24(m, 2H),2.80 and 2.71(s, 1H), 2.78 and 2.64(s, 3H), 2.38-2.03(m, 3H), 1.84-1.58and 1.47-1.36(m, 2H).

EXAMPLE 21(3)N-hydroxy-5-hydroxy-2(S)-(2-propynyl)-4(S)-[N-methyl-N-(4-chlorophenylcarbonyl)amino]pentanamide

TLC: Rf 0.26 (chloroform:methanol:acetic acid=90:10:1);

NMR (300 MHz, d₆-DMSO): δ10.59(s, 1H), 8.83 and 8.82(s, 1H),7.50-7.37(m, 4H), 4.95 and 4.80(t, J=5.4 Hz, 1H), 4.59-4.48 and3.61-3.55(m, 1H), 3.51-3.39 and 3.32-3.23(m, 2H), 2.64 and 2.78(s, 3H),2.38-2.29(m, 2 H), 2.20-2.01(m, 1H), 1.73-1.57(m, 2H).

EXAMPLE 21(4)N-hydroxy-5-ethoxymethoxy-2(S)-(2-propynyl)-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide

TLC: Rf 0.37 (chloroform:methanol=9:1);

NMR (300 MHz, d₆-DMSO): δ10.53(1H, s), 8.80(1H, brs), 8.41(1H, d, J=8.4Hz), 7.98(2H, d, J=8.7 Hz), 7.94(2H, d, J=8.7 Hz), 4.59(2H, s),4.17-4.04(1H, m), 3.54-3.43(4H, m), 2.80(1H, s), 2.36-2.23(3H, m),1.90-1.78(1H, m), 1.73-1.61(1H, m), 1.07(3H, t, J=7.2 Hz).

Formulation Example Formulation Example 1

The following components were admixed in conventional method and punchedout to obtain 100 tablets each containing 50 mg of active ingredient.

N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4- 5.0 gcyanophenyl carbonyl)amino]pentanamide Carboxymethyl Cellulose calcium(disintegrating agent) 0.2 g Magnesium stearate (lubricating agent) 0.1g Microcrystalline cellulose 4.7 g

Formulation Example 2

The following components were admixed in conventional method. Thesolution was sterilized in conventional manner, placed 5 ml portionsinto ampoules and freeze-dried to obtain 100 ampoules each containing 20mg of the active ingredient.

N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N- 2.0 g(4-cyanophenyl carbonyl)amino]pentanamide Mannitol 20 g distilled water500 ml

What is claimed is:
 1. Aminobutyric acid derivatives of the formula (I):

wherein R¹ is —COOR¹⁰, —CONHOR¹⁰, —CONHNHR¹⁰, —(CH₂)_(n)SR⁵⁰ or—Y—PO(OR⁵¹)₂; R¹⁰ is (i) hydrogen, (ii) C1-8 alkyl, (iii) C2-8 alkenyl,(iv) phenyl, (v) C1-8 alkyl substituted by phenyl or C1-8 alkoxy, or(vi) oxycarbonyl substituted by phenyl, benzyl or C1-8 alkyl; n is 0-3;R⁵⁰ is (i) hydrogen, (ii) C1-8 alkyl, (iii) —COR⁵², in which R⁵² is C1-8alkyl or phenyl, (iv) —SR⁵³, in which R⁵³ is hydrogen, C1-8 alkyl orphenyl; R⁵¹ is hydrogen, C1-8 alkyl or phenyl; Y is a single bond, —CH₂—or —O—; R², R³, R⁴, R⁵, R⁶ and R⁷ each, independently, is (1) hydrogen,(2) C1-8 alkyl, (3) C2-8 alkenyl, (4) —OR¹¹, (5) —SR¹¹, (6) —NR¹²R¹³,(7) Cyc1, (8) C1-8 alkyl substituted by one or more groups selected from—OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, (9) C2-8 alkenylsubstituted by one or more groups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³,—COR¹⁴, guanidino and Cyc1, (10) C2-8 alkynyl, (11) C1-8 alkylsubstituted by one or more groups selected from C3-8 alkenyloxy, withthe proviso that a group having a double bond at 1-position is excluded;and C3-8 alkynyloxy, with the proviso that a group having a triple bondat 1-position is excluded; or R³ and R⁴, taken together is C1-8alkylene, R⁵ and R⁶, taken together is C1-8 alkylene, R³ and R⁶, takentogether is C1-8 alkylene, R² and R³, taken together is C2-8 alkylene,R⁴ and R⁵, taken together is C2-8 alkylene, or R⁶ and R⁷, taken togetheris C2-8 alkylene; in which Cyc1 is carbocyclic ring and carbocyclic ringmay be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy,(iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atoms, (vii)cyano (viii) hydroxy, (ix) benzyloxy, (x) —NR¹⁰¹R¹⁰², in which R¹⁰¹ andR¹⁰² each, independently, is hydrogen or C1-8 alkyl, (xi) —COOR¹⁰³, inwhich R¹⁰³ is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii)trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkylor C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8alkyl substituted by phenyl or cyano, (xix) heterocyclic ring, (xx)keto, (xxi) C1-8 alkoxy substituted by —CONR¹⁰⁴R¹⁰⁵, in which R¹⁰⁴ andR¹⁰⁵ each, independently, is hydrogen, C1-8 alkyl or phenyl; R¹¹ is (i)hydrogen, (ii) C1-8 alkyl, (iii) Cyc1, (iv) —COR¹⁸, (v) C1-8 alkylsubstituted by one or more groups selected from —OR¹⁵, —SR¹⁵, —NR¹⁶R¹⁷,—COR¹⁸, guanidino and Cyc1; R¹⁵ is hydrogen, C1-8 alkyl, Cyc1 or C1-8alkyl substituted by Cyc1 or C1-8 alkoxy; R¹⁶ is hydrogen or C1-8 alkyl;R¹⁷ is hydrogen, C1-8 alkyl or —COR¹⁹, in which R¹⁹ is C1-8 alkyl, Cyc1,C1-8 alkyl substituted by Cyc1; R¹⁸ is hydroxy, C1-8 alkyl, C1-8 alkoxyor —NR²⁰R²¹, in which R²⁰ and R²¹, each independently, is hydrogen, C1-8alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1; R¹² is hydrogen, C1-8alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1; R¹³ is hydrogen, C1-8alkyl, Cyc1, C1-8 alkyl substituted by Cyc1, or —COR²², in which R²² isC1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1; R¹⁴ is hydroxy, C1-8alkyl, C1-8 alkoxy, Cyc1, C1-8 alkyl substituted by Cyc1, or —NR²³R²⁴,in which R²³ and R²⁴, each independently, is (i) hydrogen, (ii) C1-8alkyl, (iii) Cyc1 or (iv) C1-8 alkyl substituted by Cyc1 or hydroxy; (1)when R⁸ is 1) hydrogen, 2) C1-8 alkyl, 3) C1-8 alkoxycarbonyl, 4) C1-8alkyl substituted by one or more groups selected from —OR²⁶, —SR²⁶,—NR²⁷R²⁸ and —COR²⁹, or 5) C1-8 alkoxycarbonyl substituted by Cyc2, R⁹is

(2) when R⁸ is

R⁹ is 1) C1-8 alkyl, 2) C1-8 alkoxy, 3) C1-8 alkoxy substituted by Cyc2,4) C1-8 alkyl substituted by one or more groups selected from —OR²⁶,—SR²⁶, —NR²⁷R²⁸, —COR²⁹ and Cyc2, or 5)

 in which Cyc2 is carbocyclic ring and carbocyclic ring may besubstituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii)nitro, (iv) guanidino, (v) amidino, (vi) halogen atoms, (vii) cyano,(viii) hydroxy, (ix) benzyloxy, (x) —NR²⁰¹R²⁰², in which R²⁰¹ and R²⁰²each, independently, is hydrogen or C1-8 alkyl, (xi) —COOR²⁰³, in whichR²⁰³ is hydrogen or C1-8 alkyl (xii) trifluoromethyl, (xiii)trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkylor C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8alkyl substituted by phenyl or cyano, (xix) heterocyclic ring, (xx)keto, (xxi) C1-8 alkoxy substituted by —CONR²⁰⁴ R²⁰⁵, in which R²⁰⁴ andR²⁰⁵ each, independently, is hydrogen, C1-8 alkyl or phenyl; R²⁶ ishydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2; R²⁷ ishydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2; R²⁸ ishydrogen, C1-8 alkyl, Cyc2, C1-8 alkyl substituted by Cyc2, or —COR³⁰,in which R³⁰ is C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2; R²⁹is hydroxy, C1-8 alkyl, Cyc2, C1-8 alkyl substituted by Cyc2, or—NR³¹R³², in which R³¹ and R³², each independently, is hydrogen, C1-8alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2;

 is carbocyclic ring; R²⁵ is —E—G; E is 1) a single bond, 2) —CONR³³—,3) —NR³³CO—, 4) —CO—O—, 5) —O—CO—, 6) —NR³³—CO—NR³⁴—, 7) —CO—CH₂—, 8)—CO—, 9) —O—CO—NR³³—, 10) —NR³³—CO—O—, 11) —O—CO—O—, 12) —CS—NR³³—, 13)—NR³³—CS—, 14) —CS—O—, 15) —O—CS—, 16) —NR³³—CS—NR³⁴—, 17) —CS—CH₂—, 18)—CS—, 19) —O—CS—NR³³—, 20) —NR³³—CS—O—, 21) —O—CS—O—, 22) —CH₂—CH₂—, 23)—HC═CH—, 24) —C≡C—, 25) —SO₂—NR³³—, 26) —NR³³—SO₂—, 27) —SO₂—CH₂— or 28)—CH₂—SO₂—; R³³ and R³⁴, each independently, is hydrogen, C1-8 alkyl,Cyc3 or C1-8 alkyl substituted by Cyc3; Cyc3 is carbocyclic ring andcarbocyclic ring may be substituted by one or more of (i) C1-8 alkyl,(ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogenatoms, (vii) cyano, (viii) hydroxy, (ix) benzyloxy, (x) —NR³⁰¹R³⁰², inwhich R³⁰¹ and R³⁰² each, independently, is hydrogen or C1-8 alkyl, (xi)—COOR³⁰³, in which R³⁰³ is hydrogen or C1-8 alkyl, (xii)trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenylsubstituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii)phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or cyano, (xix)heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxy substituted by—CONR³⁰⁴R³⁰⁵, in which R³⁰⁴ and R³⁰⁵ each, independently, is hydrogen,C1-8 alkyl or phenyl; G is 1) hydrogen, 2) C1-8 alkyl, 3) Cyc4, 4)—OR³⁵, 5) —SR³⁵, 6) halogen atoms, 7) nitro, 8) cyano, 9) —NR³⁶R³⁷, 10)—COR³⁸, 11) C1-8 alkyl substituted by one or more groups selected fromCyc4, —OR³⁵, —SR³⁵, halogen atoms, —NR³⁶R³⁷ and —COR³⁸; in which Cyc4 iscarbocyclic ring and carbocyclic ring may be substituted by one or moreof (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v)amidino, (vi) halogen atoms, (vii) cyano, (viii) hydroxy, (ix)benzyloxy, (x) —NR⁴⁰¹R⁴⁰², in which R⁴⁰¹ and R⁴⁰² each, independently,is hydrogen or C1-8 alkyl, (xi) —COOR⁴⁰³, in which R⁴⁰³ is hydrogen orC1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv)phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi)phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted byphenyl or cyano, (xix) heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxysubstituted by —CONR⁴⁰⁴R⁴⁰⁵, in which R⁴⁰⁴ and R⁴⁰⁵ each, independently,is hydrogen, C1-8 alkyl or phenyl; R³⁵ is hydrogen, C1-8 alkyl, C1-8alkoxy, Cyc4 or C1-8 alkyl substituted by Cyc4; R³⁶ is hydrogen, C1-8alkyl, Cyc4, C1-8 alkyl substituted by Cyc4; R³⁷ is hydrogen, C1-8alkyl, Cyc4, C1-8 alkyl substituted by Cyc4, or —COR³⁹, in which R³⁹ isC1-8 alkyl, Cyc4 or C1-8 alkyl substituted by Cyc4; R³⁸ is hydroxy, C1-8alkyl, Cyc4, C1-8 alkyl substituted by Cyc4, or —NR⁴⁰R⁴¹, in which R⁴⁰and R⁴¹, each independently, is hydrogen, C1-8 alkyl, Cyc4 or C1-8 alkylsubstituted by Cyc4; or —E—G taken together, is C1-4 alkylidene; p is1-5; M is C1-8 alkylene; J is a single bond, an oxygen atom, a sulfuratom or —NR⁴²—, in which R⁴² is hydrogen or C1-8 alkyl; is a singlebond, or a double bond which prepared by two hydrogens are released, inthe case of two of R², R³, R⁴, R⁵, R⁶ and R⁷ which do not bond to a samecarbon atom but bond to a neighboring carbon, are hydrogens; with theproviso that is not a double bond, when R³ and R⁴, taken together isC1-8 alkylene, R⁵ and R⁶, taken together is C1-8 alkylene, R³ and R⁶,taken together is C1-8 alkylene; with the proviso that (1) at least oneof R², R³, R⁴, R⁵, R⁶ and R⁷ is C2-8 alkynyl, or C1-8 alkyl substitutedby one or more groups selected from C3-8 alkenyloxy and C3-8 alkynyloxy,(2) when

 is benzene, and E is a single bond, then G is not hydrogen; (3) thefollowing compound is excluded: the compound wherein R² is 2-propynyl,and R³, R⁴, R⁵, R⁶ and R⁷ each, independently, is the above groups (1)to (9) or R³ and R⁴, taken together is C1-8 alkylene, R⁵ and R⁶, takentogether is C1-8 alkylene, R³ and R⁶, taken together is C1-8 alkylene,R⁴ and R⁵, taken together is C2-8 alkylene, or R⁶ and R⁷, taken togetheris C2-8 alkylene; non-toxic acid thereof.
 2. The compound according toclaim 1, wherein R², R³, R⁴, R⁵, R⁶ and R⁷ are the same as defined inclaim 1 and at least one of R², R³, R⁴, R⁵, R⁶ and R⁷ is C1-8 alkylsubstituted by one or more groups selected from C3-8 alkenyloxy and C3-8alkynyloxy.
 3. The compound according to claim 1, wherein R², R³, R⁴,R⁵, R⁶ and R⁷ each, independently, is (1) hydrogen, (2) C1-8 alkyl, (3)C2-8 alkenyl, (4) —OR¹¹, (5) —SR¹¹, (6) —NR¹²R¹³, (7) Cyc1, (8) C1-8alkyl substituted by one or more groups selected from —OR¹¹, —SR¹¹,—NR¹²R¹³, —COR¹⁴, guanidino and Cyc1, (9) C2-8 alkenyl substituted byone or more groups selected from —OR¹¹, —SR¹¹, —NR¹²R¹³, —COR¹⁴,guanidino and Cyc1, (10) C2-8 alkynyl, or R³ and R⁴, taken together isC1-8 alkylene, R⁵ and R⁶, taken together is C1-8 alkylene, R³ and R⁶,taken together is C1-8 alkylene, R² and R³, taken together is C2-8alkylene, R⁴ and R⁵, taken together is C2-8 alkylene, or R⁶ and R⁷,taken together is C2-8 alkylene, and at least one of R², R³, R⁴, R⁵, R⁶and R⁷ is C2-8 alkynyl.
 4. A compound according to claim 2, which isselected from(1)5-ethoxymethoxy-2(R)-(2-propynyloxymethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,(2)5-ethoxymethoxy-2(R)-(2-propenyloxymethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid,(3)5-ethoxymethoxy-2(R)-(2-propynyloxymethyl)-4(S)-[N-(4-chlorophenylcarbonyl)amino]pentanoicacid,(4)N-hydroxy-5-ethoxymethoxy-2(R)-(2-propynyloxymethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,(5)N-hydroxy-5-ethoxymethoxy-2(R)-(2-propenyloxymethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,(6)N-hydroxy-5-ethoxymethoxy-2(R)-(2-propynyloxymethyl)-4(S)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,or methyl ester, t-butyl ester, benzyl ester, allyl ester, and non-toxicsalts thereof.
 5. A matrix metalloproteinase inhibitor compositioncomprising the compound of the formula (I) according to claim 1, asactive ingredient.
 6. A pharmaceutical composition for treatment ofrheumatoid diseases, arthrosteitis, osteoarthritis, unusual boneresorption, osteoporosis, periodontitis, interstitial nephritis,arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, corneaulcer, metastasis, invasion or growth of tumor cells, autoimmunedisease, disease caused by vascular emigration or infiltration ofleukocytes, arterialization, multiple sclerosis, aorta aneurysm,endometriosis, restenosis after PTCA, unstable angina, acute myocardialinfarction, or transient ischemic attack, which comprises the compoundof the formula (I) according to claim 1 as active ingredient and apharmaceutically acceptable carrier.
 7. A compound which is selectedfrom (1) 5-ethoxymethoxy-4(S)-[N-(4-iodophenylcarbonyl)amino]pentanoicacid, (2)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-methoxymethylpentanoicacid, (3)2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid, (4)5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid, (5)5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid, (6)2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid, (7)5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid, (8)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxy-phenylcarbonyl)amino]pentanoicacid, (10)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-ethoxymethylpentanoicacid, (11)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanoicacid, (12)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanoicacid, (13)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanoicacid, (14)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanoicacid, (15)5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanoicacid, (16)5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,(17)5-methoxyethoxymethoxy-2(S)-methyl-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanoicacid, (18) trans-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexanoicacid, (19)trans-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexanoicacid, (20) trans-2-[(4-nitrophenylcarbonyl)amino]cyclohexanoic acid,(21)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,(22)N-hydroxy-2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,(23)N-hydroxy-5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,(24)N-hydroxy-5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,(25)N-hydroxy-2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,(26)N-hydroxy-5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,(27)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxyphenylcarbonyl)amino]pentanamide,(29)N-hydroxy-5-ethoxymethoxy-2(R)-ethoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,(30)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,(31)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,(32)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanamide,(33)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,(34)N-hydroxy-5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanamide,(35)N-hydroxy-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,(36)N-hydroxy-2(S)-methyl-5-methoxyethoxymethoxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,(37)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,(38)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,(39)N-hydroxy-2(S)-(2-benzothiophen-3-yl)methyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,(40)N-hydroxy-2(S)-allyl-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,(41)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-bromophenylcarbonyl)amino]pentanamide,(42)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,(45)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexane,(46)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexane,(47)trans-1-(N-hydroxyaminocarbonylmethyl)-2-[(4-nitrophenylcarbonyl)amino]cyclohexane,(48)N-hydroxy-2(S)-(2-propynyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,(49)N-hydroxy-2(S)-(2-propynyl)-5-hydroxy-4(S)-[N-methyl-N-(4-bromophenylcarbonyl)amino]pentanamide,(50)N-hydroxy-5-hydroxy-2(S)-(2-propynyl)-4(S)-[N-methyl-N-(4-chlorophenylcarbonyl)amino]pentanamide,and (51)N-hydroxy-5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(S)-(2-propynyl)pentanamide,or methyl ester, t-butyl ester, benzyl ester, allyl ester, and non-toxicsalts thereof.
 8. A matrix metalloproteinase inhibitor compositioncomprising the compound according to claim 7, as active ingredient.
 9. Apharmaceutical composition for treatment of rheumatoid diseases,arthrosteitis, osteoarthritis, unusual bone resorption, osteoporosis,periodontitis, interstitial nephritis, arteriosclerosis, pulmonaryemphysema, cirrhosis, cornea injury, cornea ulcer, metastasis, invasionor growth of tumor cells, autoimmune disease, disease caused by vascularemigration or infiltration of leukocytes, arterialization, multiplesclerosis, aorta aneurysm, endometriosis, restenosis after PTCA,unstable angina, acute myocardial infarction, or transient ischemicattack, which comprises the compound according to claim 7 as activeingredient and a pharmaceutically acceptable carrier.